ACTION: Denial of petition to initiate proceedings to reschedule
marijuana.

SUMMARY: By letter dated June 21, 2011, the Drug Enforcement
Administration (DEA) denied a petition to initiate rulemaking
proceedings to reschedule marijuana.\1\ Because DEA believes that this
matter is of particular interest to members of the public, the agency
is publishing below the letter sent to the petitioner (denying the
petition), along with the supporting documentation that was attached to
the letter.

On October 9, 2002, you petitioned the Drug Enforcement
Administration (DEA) to initiate rulemaking proceedings under the
rescheduling provisions of the Controlled Substances Act (CSA).
Specifically, you petitioned DEA to have marijuana removed from
schedule I of the CSA and rescheduled as cannabis in schedule III, IV
or V.

You requested that DEA remove marijuana from schedule I based on
your assertion that:

(1) Cannabis has an accepted medical use in the United States;

(2) Cannabis is safe for use under medical supervision;

(3) Cannabis has an abuse potential lower than schedule I or II
drugs; and

(4) Cannabis has a dependence liability that is lower than schedule
I or II drugs.

In accordance with the CSA rescheduling provisions, after gathering
the necessary data, DEA requested a scientific and medical evaluation
and scheduling recommendation from the Department of Health and Human
Services (DHHS). DHHS concluded that marijuana has a high potential for
abuse, has no accepted medical use in the United States, and lacks an
acceptable level of safety for use even under medical supervision.
Therefore, DHHS recommended that marijuana remain in schedule I. The
scientific and medical evaluation and scheduling recommendation that
DHHS submitted to DEA is attached hereto.

Based on the DHHS evaluation and all other relevant data, DEA has
concluded that there is no substantial evidence that marijuana should
be removed from schedule I. A document prepared by DEA addressing these
materials in detail also is attached hereto. In short, marijuana
continues to meet the criteria for schedule I control under the CSA
because:

(1) Marijuana has a high potential for abuse. The DHHS evaluation
and the additional data gathered by DEA show that marijuana has a high
potential for abuse.

(2) Marijuana has no currently accepted medical use in treatment in
the United States. According to established case law, marijuana has no
"currently accepted medical use" because: The drug's chemistry is not
known and reproducible; there are no adequate safety studies; there are
no adequate and well-controlled studies proving efficacy; the drug is
not accepted by qualified experts; and the scientific evidence is not
widely available.

(3) Marijuana lacks accepted safety for use under medical
supervision. At present, there are no U.S. Food and Drug Administration
(FDA)-approved marijuana products, nor is marijuana under a New Drug
Application (NDA) evaluation at the FDA for any indication. Marijuana
does not have a currently accepted medical use in treatment in the
United States or a currently accepted medical use with severe
restrictions. At this time, the known risks of marijuana use have not
been shown to be outweighed by specific benefits in well-controlled
clinical trials that scientifically evaluate safety and efficacy.

You also argued that cannabis has a dependence liability that is
lower than schedule I or II drugs. Findings as to the physical or
psychological dependence of a drug are only one of eight factors to be
considered. As discussed further in the attached documents, DHHS states
that long-term, regular use of marijuana can lead to physical
dependence and withdrawal following discontinuation as well as psychic
addiction or dependence.

The statutory mandate of 21 U.S.C. 812(b) is dispositive. Congress
established only one schedule, schedule I, for drugs of abuse with "no
currently accepted medical use in treatment in the United States" and
"lack of accepted safety for use under medical supervision." 21
U.S.C. 812(b).

Accordingly, and as set forth in detail in the accompanying DHHS
and DEA documents, there is no statutory basis under the CSA for DEA to
grant your petition to initiate rulemaking proceedings to reschedule
marijuana. Your petition is, therefore, hereby denied.

Sincerely,

Michele M. Leonhart, Administrator.

Attachments:

Marijuana. Scheduling Review Document: Eight Factor Analysis

Basis for the recommendation for maintaining marijuana in schedule I
of the Controlled Substances Act

Date: June 30, 2011

Michele M. Leonhart Administrator

Department of Health and Human Services,
Office of the Secretary Assistant Secretary for Health, Office of
Public Health and Science Washington, D.C. 20201.

This is in response to your request of July 2004, and pursuant
to the Controlled Substances Act (CSA), 21 U.S.C. 811(b), (c), and
(f), the Department of Health and Human Services (DHHS) recommends
that marijuana continue to be subject to control under Schedule I of
the CSA.

Marijuana is currently controlled under Schedule I of the CSA.
Marijuana continues to meet the three criteria for placing a
substance in Schedule I of the CSA under 21 U.S.C. 812(b)(l). As
discussed in the attached analysis, marijuana has a high potential
for abuse, has no currently accepted medical use in treatment in the
United States, and has a lack of an accepted level of safety for use
under medical supervision. Accordingly, HHS recommends that
marijuana continue to be subject to control under Schedule I of the
CSA. Enclosed is a document prepared by FDA's Controlled Substance
Staff that is the basis for this recommendation.

Should you have any questions regarding this recommendation,
please contact Corinne P. Moody, of the Controlled Substance Staff,
Center for Drug Evaluation and Research. Ms. Moody can be reached at
301-827-1999.

Sincerely yours,

John O. Agwunobi,Assistant Secretary for Health.

Enclosure:

[[Page 40553]]

Basis for the Recommendation for Maintaining Marijuana in Schedule I
of the Controlled Substances Act

BASIS FOR THE RECOMMENDATION FOR MAINTAINING MARIJUANA IN SCHEDULE I OF
THE CONTROLLED SUBSTANCES ACT

On October 9, 2002, the Coalition for Rescheduling Cannabis
(hereafter known as the Coalition) submitted a petition to the Drug
Enforcement Administration (DEA) requesting that proceedings be
initiated to repeal the rules and regulations that place marijuana
in Schedule I of the Controlled Substances Act (CSA). The petition
contends that cannabis has an accepted medical use in the United
States, is safe for use under medical supervision, and has an abuse
potential and a dependency liability that is lower than Schedule I
or II drugs. The petition requests that marijuana be rescheduled as
"cannabis" in either Schedule III, IV, or V of the CSA. In July
2004, the DEA Administrator requested that the Department of Health
and Human Services (HHS) provide a scientific and medical evaluation
of the available information and a scheduling recommendation for
marijuana, in accordance with the provisions of 21 U.S.C. 811(b).

In accordance with 21 U.S.C. 811(b), DEA has gathered
information related to the control of marijuana (Cannabis sativa)
\2\ under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary is
required to consider in a scientific and medical evaluation eight
factors determinative of control under the CSA. Following
consideration of the eight factors, if it is appropriate, the
Secretary must make three findings to recommend scheduling a
substance in the CSA. The findings relate to a substance's abuse
potential, legitimate medical use, and safety or dependence
liability.

\2\ The CSA defines marijuana as the following:
all parts of the plant Cannabis Sativa L., whether growing or
not; the seeds thereof; the resin extracted from any part of such
plant; and every compound, manufacture, salt, derivative, mixture,
or preparation of such plant, its seeds or resin. Such term does not
include the mature stalks of such plant, fiber produced from such
stalks, oil or cake made from the seeds of such plant, any other
compound, manufacture, salt, derivative, mixture, or preparation of
such mature stalks (except the resin extracted there from), fiber,
oil, or cake, or the sterilized seed of such plant which is
incapable of germination (21 U.S.C. 802(16)).

Administrative responsibilities for evaluating a substance for
control under the CSA are performed by the Food and Drug
Administration (FDA), with the concurrence of the National Institute
on Drug Abuse (NIDA), as described in the Memorandum of
Understanding (MOU) of March 8, 1985 (50 FR 9518-20).

In this document, FDA recommends the continued control of
marijuana in Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c),
the eight factors pertaining to the scheduling of marijuana are
considered below.

1. ITS ACTUAL OR RELATIVE POTENTIAL FOR ABUSE

The first factor the Secretary must consider is marijuana's
actual or relative potential for abuse. The term "abuse" is not
defined in the CSA. However, the legislative history of the CSA
suggests the following in determining whether a particular drug or
substance has a potential for abuse:

a. Individuals are taking the substance in amounts sufficient to
create a hazard to their health or to the safety of other
individuals or to the community.

b. There is a significant diversion of the drug or substance
from legitimate drug channels.

c. Individuals are taking the substance on their own initiative
rather than on the basis of medical advice from a practitioner
licensed by law to administer such substances.

d. The substance is so related in its action to a substance
already listed as having a potential for abuse to make it likely
that it will have the same potential for abuse as such substance,
thus making it reasonable to assume that there may be significant
diversions from legitimate channels, significant use contrary to or
without medical advice, or that it has a substantial capability of
creating hazards to the health of the user or to the safety of the
community.

In considering these concepts in a variety of scheduling
analyses over the last three decades, the Secretary has analyzed a
range of factors when assessing the abuse liability of a substance.
These factors have included the prevalence and frequency of use in
the general public and in specific sub-populations, the amount of
the material that is available for illicit use, the ease with which
the substance may be obtained or manufactured, the reputation or
status of the substance "on the street," as well as evidence
relevant to population groups that may be at particular risk.

Abuse liability is a complex determination with many dimensions.
There is no single test or assessment procedure that, by itself,
provides a full and complete characterization. Thus, no single
measure of abuse liability is ideal. Scientifically, a comprehensive
evaluation of the relative abuse potential of a drug substance can
include consideration of the drug's receptor binding affinity,
preclinical pharmacology, reinforcing effects, discriminative
stimulus effects, dependence producing potential, pharmacokinetics
and route of administration, toxicity, assessment of the clinical
efficacy-safety database relative to actual abuse, clinical abuse
liability studies, and the public health risks following
introduction of the substance to the general population. It is
important to note that abuse may exist independent of a state of
tolerance or physical dependence, because drugs may be abused in
doses or in patterns that do not induce these phenomena. Animal
data, human data, and epidemiological data are all used in
determining a substance's abuse liability. Epidemiological data can
also be an important indicator of actual abuse. Finally, evidence of
clandestine production and illicit trafficking of a substance are
also important factors.

a. There is evidence that individuals are taking the substance
in amounts sufficient to create a hazard to their health or to the
safety of other individuals or to the community.

Marijuana is a widely abused substance. The pharmacology of the
psychoactive constituents of marijuana, including delta\9\-
tetrahydrocannabinol (delta\9\-THC), the primary psychoactive
ingredient in marijuana, has been studied extensively in animals and
humans and is discussed in more detail below in Factor 2,
"Scientific Evidence of its Pharmacological Effects, if Known."
Data on the extent of marijuana abuse are available from HHS through
NIDA and the Substance Abuse and Mental Health Services
Administration (SAMHSA). These data are discussed in detail under
Factor 4, "Its History and Current Pattern of Abuse;" Factor 5,
"The Scope, Duration, and Significance of Abuse;" and Factor 6,
"What, if any, Risk There is to the Public Health?"

According to SAMHSA's 2004 National Survey on Drug Use and
Health (NSDUH; the database formerly known as the National Household
Survey on Drug Abuse (NHSDA)), the latest year for which complete
data are available, 14.6 million Americans have used marijuana in
the past month. This is an increase of 3.4 million individuals since
1999, when 11.2 million individuals reported using marijuana
monthly. (See the discussion of NSDUH data under Factor 4).

The Drug Abuse Warning Network (DAWN), sponsored by SAMHSA, is a
national probability survey of U.S. hospitals with emergency
departments (EDs) designed to obtain information on ED visits in
which recent drug use is implicated; 2003 is the latest year for
which complete data are available. Marijuana was involved in 79,663
ED visits (13 percent of drug-related visits). There are a number of
risks resulting from both acute and chronic use of marijuana which
are discussed in full below under Factors 2 and 6.

b. There is significant diversion of the substance from
legitimate drug channels.

At present, cannabis is legally available through legitimate
channels for research purposes only and thus has a limited potential
for diversion. In addition, the lack of significant diversion of
investigational supplies may result from the ready availability of
illicit cannabis of equal or greater quality. The magnitude of the
demand for illicit marijuana is evidenced by DEA/Office of National
Drug Control Policy (ONDCP) seizure statistics. Data on marijuana
seizures can often highlight trends in the overall trafficking
patterns. DEA's Federal-Wide Drug Seizure System (FDSS) provides
information on total federal drug seizures. FDSS reports total
federal seizures of 2,700,282 pounds of marijuana in 2003, the
latest year for which complete data are available (DEA, 2003). This
represents nearly a doubling of marijuana seizures since 1995, when
1,381,107 pounds of marijuana were seized by federal agents.

c. Individuals are taking the substance on their own initiative
rather than on the basis of medical advice from a practitioner
licensed by law to administer such substances.

[[Page 40554]]

The 2004 NSDUH data show that 14.6 million American adults use
marijuana on a monthly basis (SAMHSA, 2004), confirming that
marijuana has reinforcing properties for many individuals. The FDA
has not evaluated or approved a new drug application (NDA) for
marijuana for any therapeutic indication, although several
investigational new drug (IND) applications are currently active.
Based on the large number of individuals who use marijuana, it can
be concluded that the majority of individuals using cannabis do so
on their own initiative, not on the basis of medical advice from a
practitioner licensed to administer the drug in the course of
professional practice.

d. The substance is so related in its action to a substance
already listed as having a potential for abuse to make it likely
that it will have the same potential for abuse as such substance,
thus making it reasonable to assume that there may be significant
diversions from legitimate channels, significant use contrary to or
without medical advice, or that it has a substantial capability of
creating hazards to the health of the user or to the safety of the
community.

The primary psychoactive compound in botanical marijuana is
delta\9\-THC. Other cannabinoids also present in the marijuana plant
likely contribute to the psychoactive effects.

There are two drug products containing cannabinoid compounds
that are structurally related to the active components in marijuana.
Both are controlled under the CSA. Marinol is a Schedule III drug
product containing synthetic delta\9\-THC, known generically as
dronabinol, formulated in sesame oil in soft gelatin capsules.
Dronabinol is listed in Schedule I. Marinol was approved by the FDA
in 1985 for the treatment of two medical conditions: nausea and
vomiting associated with cancer chemotherapy in patients that had
failed to respond adequately to conventional anti-emetic treatments,
and for the treatment of anorexia associated with weight loss in
patients with acquired immunodeficiency syndrome or AIDS. Cesamet is
a drug product containing the Schedule II substance, nabilone, that
was approved for marketing by the FDA in 1985 for the treatment of
nausea and vomiting associated with cancer chemotherapy. All other
structurally related cannabinoids in marijuana are already listed as
Schedule I drugs under the CSA.

2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN

The second factor the Secretary must consider is scientific
evidence of marijuana's pharmacological effects. There are abundant
scientific data available on the neurochemistry, toxicology, and
pharmacology of marijuana. This section includes a scientific
evaluation of marijuana's neurochemistry, pharmacology, and human
and animal behavioral, central nervous system, cognitive,
cardiovascular, autonomic, endocrinological, and immunological
system effects. The overview presented below relies upon the most
current research literature on cannabinoids.

Neurochemistry and Pharmacology of Marijuana

Some 483 natural constituents have been identified in marijuana,
including approximately 66 compounds that are classified as
cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not known
to exist in plants other than marijuana, and most of the cannabinoid
compounds that occur naturally have been identified chemically.
Delta\9\-THC is considered the major psychoactive cannabinoid
constituent of marijuana (Wachtel et al., 2002). The structure and
function of delta\9\-THC was first described in 1964 by Gaoni and
Mechoulam.

The site of action of delta\9\-THC and other cannabinoids was
verified with the cloning of cannabinoid receptors, first from rat
brain tissue (Matsuda et al., 1990) and then from human brain tissue
(Gerard et al., 1991). Two cannabinoid receptors, CB1 and
CB2, have subsequently been characterized (Piomelli,
2005).

Autoradiographic studies have provided information on the
distribution of cannabinoid receptors. CB1 receptors are
found in the basal ganglia, hippocampus, and cerebellum of the brain
(Howlett et al., 2004) as well as in the immune system. It is
believed that the localization of these receptors may explain
cannabinoid interference with movement coordination and effects on
memory and cognition. The concentration of CB1 receptors
is considerably lower in peripheral tissues than in the central
nervous system (Henkerham et al., 1990 and 1992).

CB2 receptors are found primarily in the immune
system, predominantly in B lymphocytes and natural killer cells
(Bouaboula et al., 1993). It is believed that the CB2-
type receptor is responsible for mediating the immunological effects
of cannabinoids (Galiegue et al., 1995).

However, CB2 receptors also have recently been
localized in the brain, primarily in the cerebellum and hippocampus
(Gong et al., 2006).

The cannabinoid receptors belong to the family of G-protein-
coupled receptors and present a typical seven transmembrane-spanning
domain structure. Many G-protein-coupled receptors are linked to
adenylate cyclase either positively or negatively, depending on the
receptor system. Cannabinoid receptors are linked to an inhibitory
G-protein (Gi), so that when the receptor is activated, adenylate
cyclase activity is inhibited, which prevents the conversion of
adenosine triphosphate (ATP)to the second messenger cyclic adenosine
monophosphate (cAMP). Examples of inhibitory-coupled receptors
include: opioid, muscarinic cholinergic, alpha 2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).

It has been shown that CB1, but not CB2
receptors, inhibit N- and P/Q type calcium channels and activate
inwardly rectifying potassium channels (Mackie et al., 1995;
Twitchell et al., 1997). Inhibition of the N-type calcium channels
decreases neurotransmitter release from several tissues and this may
be the mechanism by which cannabinoids inhibit acetylcholine,
norepinephrine, and glutamate release from specific areas of the
brain. These effects might represent a potential cellular mechanism
underlying the antinociceptive and psychoactive effects of
cannabinoids (Ameri, 1999). When cannabinoids are given subacutely
to rats, there is a down-regulation of CB1 receptors, as
well as a decrease in GTPgammaS binding, the second messenger system
coupled to CB1 receptors (Breivogel et al., 2001).

Delta\9\-THC displays similar affinity for CB1 and
CB2 receptors but behaves as a weak agonist for
CB2 receptors, based on inhibition of adenylate cyclase.
The identification of synthetic cannabinoid ligands that selectively
bind to CB2 receptors but do not have the typical
delta\9\-THC-like psychoactive properties suggests that the
psychotropic effects of cannabinoids are mediated through the
activation of CB1-receptors (Hanus et al., 1999).
Naturally-occurring cannabinoid agonists, such as delta\9\-THC, and
the synthetic cannabinoid agonists such as WIN-55,212-2 and CP-
55,940 produce hypothermia, analgesia, hypoactivity, and cataplexy
in addition to their psychoactive effects.

In 2000, two endogenous cannabinoid receptor agonists,
anandamide and arachidonyl glycerol (2-AG), were discovered.
Anandamide is a low efficacy agonist (Breivogel and Childers, 2000),
2-AG is a highly efficacious agonist (Gonsiorek et al., 2000).
Cannabinoid endogenous ligands are present in central as well as
peripheral tissues. The action of the endogenous ligands is
terminated by a combination of uptake and hydrolysis. The
physiological role of endogenous cannabinoids is an active area of
research (Martin et al., 1999).

Progress in cannabinoid pharmacology, including further
characterization of the cannabinoid receptors, isolation of
endogenous cannabinoid ligands, synthesis of agonists and
antagonists with variable affinity, and selectivity for cannabinoid
receptors, provide the foundation for the potential elucidation of
cannabinoid-mediated effects and their relationship to psychomotor
disorders, memory, cognitive functions, analgesia, anti-emesis,
intraocular and systemic blood pressure modulation, bronchodilation,
and inflammation.

Central Nervous System Effects

Human Physiological and Psychological Effects

Subjective Effects

The physiological, psychological, and behavioral effects of
marijuana vary among individuals. Common responses to cannabinoids,
as described by Adams and Martin (1996) and others (Hollister, 1986
and 1988; Institute of Medicine, 1982) are listed below:

5) Heightened imagination leading to a subjective sense of
increased creativity

6) Time distortions

7) Illusions, delusions, and hallucinations, especially at high
doses

8) Impaired judgment, reduced co-ordination and ataxia, which
can impede driving ability or lead to an increase in risk-taking
behavior

9) Emotional lability, incongruity of affect, dysphoria,
disorganized thinking, inability to converse logically, agitation,
paranoia, confusion, restlessness, anxiety, drowsiness, and panic
attacks, especially in inexperienced users or in those who have
taken a large dose

10) Increased appetite and short-term memory impairment
These subjective responses to marijuana are pleasurable to many
humans and are associated with drug-seeking and drug-taking
(Maldonado, 2002).

The short-term perceptual distortions and psychological
alterations produced by marijuana have been characterized by some
researchers as acute or transient psychosis (Favrat et al., 2005).
However, the full response to cannabinoids is dissimilar to the DSM-
IV-TR criteria for a diagnosis of one of the psychotic disorders
(DSM-IV-TR, 2000).

As with many psychoactive drugs, an individual's response to
marijuana can be influenced by that person's medical/psychiatric
history and history with drugs. Frequent marijuana users (greater
than 100 times) were better able to identify a drug effect from low
dose delta\9\-THC than infrequent users (less than 10 times) and
were less likely to experience sedative effects from the drug (Kirk
and deWit, 1999). Dose preferences have been demonstrated for
marijuana in which higher doses (1.95 percent delta\9\-THC) are
preferred over lower doses (0.63 percent delta\9\-THC) (Chait and
Burke, 1994).

Behavioral Impairment

Acute administration of smoked marijuana impairs performance on
tests of learning, associative processes, and psychomotor behavior
(Block et al., 1992). These data demonstrate that the short-term
effects of marijuana can interfere significantly with an
individual's ability to learn in the classroom or to operate motor
vehicles. Administration to human volunteers of 290 micrograms per
kilogram ([mu]g/kg) delta\9\-THC in a smoked marijuana cigarette
resulted in impaired perceptual motor speed and accuracy, two skills
that are critical to driving ability (Kurzthaler et al., 1999).
Similarly, administration of 3.95 percent delta\9\-THC in a smoked
marijuana cigarette increased disequilibrium measures, as well as
the latency in a task of simulated vehicle braking, at a rate
comparable to an increase in stopping distance of 5 feet at 60 mph
(Liguori et al., 1998).

The effects of marijuana may not fully resolve until at least 1
day after the acute psychoactive effects have subsided, following
repeated administration. Heishman et al. (1990) showed that
impairment on memory tasks persists for 24 hours after smoking
marijuana cigarettes containing 2.57 percent delta\9\-THC. However,
Fant et al. (1998) showed minimal residual alterations in subjective
or performance measures the day after subjects were exposed to 1.8
percent or 3.6 percent smoked delta\9\-THC.

The effects of chronic marijuana use have also been
investigated. Marijuana did not appear to have residual effects on
performance of a comprehensive neuropsychological battery when 54
monozygotic male twins (one of whom used marijuana, one of whom did
not) were compared 1-20 years after cessation of marijuana use
(Lyons et al., 2004). This conclusion is similar to the results from
an earlier study of marijuana's effects on cognition in 1,318
participants over a 15-year period, where there was no evidence of
long-term residual effects (Lyketsos et al., 1999). In contrast,
Solowij et al. (2002) demonstrated that 51 long-term cannabis users
did less well than 33 non-using controls or 51 short-term users on
certain tasks of memory and attention, but users in this study were
abstinent for only 17 hours at time of testing. A recent study noted
that heavy, frequent cannabis users, abstinent for at least 24
hours, performed significantly worse than controls on verbal memory
and psychomotor speed tests (Messinis et al, 2006).

Pope et al. (2003) reported that no differences were seen in
neuropsychological performance in early- or late-onset users
compared to non-using controls, after adjustment for intelligence
quotient (IQ). In another cohort of chronic, heavy marijuana users,
some deficits were observed on memory tests up to a week following
supervised abstinence, but these effects disappeared by day 28 of
abstinence (Harrison et al., 2002). The authors concluded that,
"cannabis-associated cognitive deficits are reversible and related
to recent cannabis exposure, rather than irreversible and related to
cumulative lifetime use." Other investigators have reported
neuropsychological deficits in memory, executive functioning,
psychomotor speed, and manual dexterity in heavy marijuana smokers
who had been abstinent for 28 days (Bolla et al., 2002). A follow up
study of heavy marijuana users noted decision-making deficits after
25 days of abstinence (Bolla et al., 2005). Finally, when IQ was
contrasted in adolescents at 9-12 years and at 17-20 years, current
heavy marijuana users showed a 4-point reduction in IQ in later
adolescence compared to those who did not use marijuana (Fried et
al., 2002).

Age of first use may be a critical factor in persistent
impairment resulting from chronic marijuana use. Individuals with a
history of marijuana-only use that began before the age of 16 were
found to perform more poorly on a visual scanning task measuring
attention than individuals who started using marijuana after age 16
(Ehrenreich et al., 1999). Kandel and Chen (2000) assert that the
majority of early-onset marijuana users do not go on to become heavy
users of marijuana, and those that do tend to associate with
delinquent social groups.

Heavy marijuana users were contrasted with an age matched
control group in a case-control design. The heavy users reported
lower educational achievement and lower income than controls, a
difference that persisted after confounding variables were taken
into account. Additionally, the users also reported negative effects
of marijuana use on cognition, memory, career, social life, and
physical and mental health (Gruber et al., 2003).

Association with Psychosis

Extensive research has been conducted recently to investigate
whether exposure to marijuana is associated with schizophrenia or
other psychoses. While many studies are small and inferential, other
studies in the literature utilize hundreds to thousands of subjects.

At present, the data do not suggest a causative link between
marijuana use and the development of psychosis. Although some
individuals who use marijuana have received a diagnosis of
psychosis, most reports conclude that prodromal symptoms of
schizophrenia appear prior to marijuana use (Schiffman et al.,
2005). When psychiatric symptoms are assessed in individuals with
chronic psychosis, the "schizophrenic cluster" of symptoms is
significantly observed among individuals who do not have a history
of marijuana use, while "mood cluster" symptoms are significantly
observed in individuals who do have a history of marijuana use
(Maremmani et al., 2004).

In the largest study evaluating the link between psychosis and
drug use, 3 percent of 50,000 Swedish conscripts who used marijuana
more than 50 times went on to develop schizophrenia (Andreasson et
al., 1987). This was interpreted by the authors to suggest that
marijuana use increased the risk for the disorder only among those
individuals who were predisposed to develop psychosis. A similar
conclusion was drawn when the prevalence of schizophrenia was
modeled against marijuana use across birth cohorts in Australia
between the years 1940 to 1979 (Degenhardt et al., 2003). Although
marijuana use increased over time in adults born during the 4-decade
period, there was not a corresponding increase in diagnoses for
psychosis in these individuals. The authors conclude that marijuana
may precipitate schizophrenic disorders only in those individuals
who are vulnerable to developing psychosis. Thus, marijuana per se
does not appear to induce schizophrenia in the majority of
individuals who try or continue to use the drug.

However, as might be expected, the acute intoxication produced
by marijuana does exacerbate the perceptual and cognitive deficits
of psychosis in individuals who have been previously diagnosed with
the condition (Schiffman et al., 2005; Hall et al., 2004; Mathers
and Ghodse, 1992; Thornicroft, 1990). This is consistent with a 25-
year longitudinal study of over 1,000 individuals who had a higher
rate of experiencing some symptoms of psychosis (but who did not
receive a diagnosis of psychosis) if they were daily marijuana users
than if they were not (Fergusson et al., 2005). A shorter, 3-year
longitudinal study with over 4,000 subjects similarly showed that
psychotic symptoms, but not diagnoses, were more prevalent in
subjects who used marijuana (van Os et al., 2002).

[[Page 40556]]

Additionally, schizophrenic individuals stabilized with
antipsychotics do not respond differently to marijuana than healthy
controls (D'Souza et al., 2005), suggesting that psychosis and/or
antipsychotics do not biochemically alter cannabinoid systems in the
brain.

Interestingly, cannabis use prior to a first psychotic episode
appeared to spare neurocognitive deficits compared to patients who
had not used marijuana (Stirling et al., 2005). Although adolescents
diagnosed with a first psychotic episode used more marijuana than
adults who had their first psychotic break, adolescents and adults
had similar clinical outcomes 2 years later (Pencer et al., 2005).

Heavy marijuana users, though, do not perform differently than
non-users on the Stroop task, a classic psychometric instrument that
measures executive cognitive functioning. Since psychotic
individuals do not perform the Stroop task well, alterations in
executive functioning consistent with a psychotic profile were not
apparent following chronic exposure to marijuana (Gruber and
Yurgelun-Todd, 2005; Eldreth et al., 2004).

Alteration in Brain Structure

Although evidence suggests that some drugs of abuse can lead to
changes in the density or structure of the brain in humans, there
are currently no data showing that exposure to marijuana can induce
such alterations. A recent comparison of long-term marijuana smokers
to non-smoking control subjects using magnetic resonance imaging
(MRI) did not reveal any differences in the volume of grey or white
matter, in the hippocampus, or in cerebrospinal fluid volume,
between the two groups (Tzilos et al., 2005).

Behavioral Effects of Prenatal Exposure

The impact of in utero marijuana exposure on performance in a
series of cognitive tasks has been studied in children at different
stages of development. However, since many marijuana users have
abused other drugs, it is difficult to determine the specific impact
of marijuana on prenatal exposure.

Differences in several cognitive domains distinguished the 4-
year-old children of heavy marijuana users. In particular, memory
and verbal measures are negatively associated with maternal
marijuana use (Fried and Watkinson, 1987). Maternal marijuana use is
predictive of poorer performance on abstract/visual reasoning tasks,
although it is not associated with an overall lowered IQ in 3-year
old children (Griffith et al., 1994). At 6 years of age, prenatal
marijuana history is associated with an increase in omission errors
on a vigilance task, possibly reflecting a deficit in sustained
attention (Fried et al., 1992). When the effect of prenatal exposure
in 9-12 year old children is analyzed, in utero marijuana exposure
is negatively associated with executive function tasks that require
impulse control, visual analysis, and hypothesis testing, and it is
not associated with global intelligence (Fried et al., 1998).

Marijuana as a "Gateway Drug"

The Institute of Medicine (IOM) reported that the widely held
belief that marijuana is a "gateway drug," leading to subsequent
abuse of other illicit drugs, lacks conclusive evidence (Institute
of Medicine, 1999). Recently, Fergusson et al. (2005) in a 25-year
study of 1,256 New Zealand children concluded that use of marijuana
correlates to an increased risk of abuse of other drugs, including
cocaine and heroin. Other sources, however, do not support a direct
causal relationship between regular marijuana and other illicit drug
use. In general, such studies are selective in recruiting
individuals who, in addition to having extensive histories of
marijuana use, are influenced by myriad social, biological, and
economic factors that contribute to extensive drug abuse (Hall and
Lynskey, 2005). For most studies that test the hypothesis that
marijuana causes abuse of harder drugs, the determinative measure of
choice is any drug use, rather than DSM-IV-TR criteria for drug
abuse or dependence (DSM-IV-TR, 2000).

According to Golub & Johnson (2001), the rate of progression to
hard drug use by youth born in the 1970's, as opposed to youth born
between World War II and the 1960's, is significantly decreased,
although overall marijuana use among youth appears to be increasing.
Nace et al. (1975) reported that even in the Vietnam-era soldiers
who extensively abused marijuana and heroin, there was a lack of
correlation of a causal relationship demonstrating marijuana use
leading to heroin addiction. A recent longitudinal study of 708
adolescents demonstrated that early onset marijuana use did not lead
to problematic drug use (Kandel and Chen, 2000). Similarly, among
2,446 adolescents followed longitudinally, cannabis dependence was
uncommon but when it did occur, it was predicted primarily by
parental death, deprived socio-economic status, and baseline use of
illicit drugs other than marijuana (von Sydow et al., 2002).

Animal behavioral effects

Self-Administration

Self-administration is a method that assesses whether a drug
produces rewarding effects that increase the likelihood of
behavioral responses in order to obtain additional drug. Drugs that
are self-administered by animals are likely to produce rewarding
effects in humans, which is indicative of abuse liability.
Generally, a good correlation exists between those drugs that are
self-administered by rhesus monkeys and those that are abused by
humans (Balster and Bigelow, 2003).

Interestingly, self-administration of hallucinogenic-like drugs,
such as cannabinoids, lysergic acid diethylamide (LSD), and
mescaline, has been difficult to demonstrate in animals (Yanagita,
1980). However, when it is known that humans voluntarily consume a
particular drug (such as cannabis) for its pleasurable effects, the
inability to establish self-administration with that drug in animals
has no practical importance in the assessment of abuse potential.
This is because the animal test is a predictor of human behavioral
response in the absence of naturalistic data.

The experimental literature generally reports that na[iuml]ve
animals will not self-administer cannabinoids unless they have had
previous experience with other drugs of abuse. However, when
squirrel monkeys are first trained to self-administer intravenous
cocaine, they will continue to bar-press at the same rate as when
delta\9\-THC is substituted for cocaine, at doses that are
comparable to those used by humans who smoke marijuana (Tanda et
al., 2000). This effect is blocked by the cannabinoid receptor
antagonist, SR 141716. New studies show that monkeys without a
history of any drug exposure can be successfully trained to self-
administer delta\9\-THC intravenously (Justinova et al., 2003). The
maximal rate of responding is 4 [mu]g/kg/injection, which is 2-3
times greater than that observed in previous studies using cocaine-
experienced monkeys.

These data demonstrate that under specific pretreatment
conditions, an animal model of reinforcement by cannabinoids now
exists for future investigations. Rats will self-administer
delta\9\-THC when it is applied intracerebroventricularly (i.c.v.),
but only at the lowest doses tested (0.01-0.02 [mu]g/infusion)
(Braida et al., 2004). This effect is antagonized by the cannabinoid
antagonist SR141716 and by the opioid antagonist naloxone (Braida et
al., 2004). Additionally, mice will self-administer WIN 55212, a
CB1 receptor agonist with a non-cannabinoid structure
(Martellotta et al., 1998).

There may be a critical dose-dependent effect, though, since
aversive effects, rather than reinforcing effects, have been
described in rats that received high doses of WIN 55212 (Chaperon et
al., 1998) or delta\9\-THC (Sanudo-Pena et al., 1997). SR 141716
reversed these aversive effects in both studies.

Conditioned Place Preference

Conditioned place preference (CPP) is a less rigorous method
than self-administration of determining whether drugs have rewarding
properties. In this behavioral test, animals are given the
opportunity to spend time in two distinct environments: one where
they previously received a drug and one where they received a
placebo. If the drug is reinforcing, animals will choose to spend
more time in the environment paired with the drug than the one
paired with the placebo, when both options are presented
simultaneously.

Animals show CPP to delta\9\-THC, but only at the lowest doses
tested (0.075-0.75 mg/kg, i.p.) (Braida et al., 2004). This effect
is antagonized by the cannabinoid antagonist, SR141716, as well as
by the opioid antagonist, naloxone (Braida et al., 2004). However,
SR141716 may be a partial agonist, rather than a full antagonist,
since it is also able to induce CPP (Cheer et al., 2000).
Interestingly, in knockout mice, animals without [mu]-opioid
receptors do not develop CPP to delta\9\-THC (Ghozland et al.,
2002).

Drug Discrimination Studies

Drug discrimination is a method in which animals indicate
whether a test drug produces physical or psychic perceptions similar
to those produced by a known drug of abuse. In this test, an animal
learns to press one bar when it receives the known drug of abuse and
another bar when it receives placebo. A challenge session with the
test drug determines which of the two

[[Page 40557]]

bars the animal presses more often, as an indicator of whether the
test drug is like the known drug of abuse.

Animals, including monkeys and rats (Gold et al., 1992), as well
as humans (Chait, 1988), can discriminate cannabinoids from other
drugs or placebo. Discriminative stimulus effects of delta\9\-THC
are pharmacologically specific for marijuana-containing cannabinoids
(Balster and Prescott, 1992; Barnett et al., 1985; Browne and
Weissman, 1981; Wiley et al., 1993; Wiley et al., 1995).
Additionally, the major active metabolite of delta\9\-THC, 11-
hydroxy-delta\9\-THC, also generalizes to the stimulus cue elicited
by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other
cannabinoids found in marijuana also fully substitute for delta\9\-
THC.

The discriminative stimulus effects of the cannabinoid group
appear to provide unique effects because stimulants, hallucinogens,
opioids, benzodiazepines, barbiturates, NMDA antagonists, and
antipsychotics do not fully substitute for delta\9\-THC.

Tolerance and Physical Dependence

Tolerance is a state of adaptation in which exposure to a drug
induces changes that result in a diminution of one or more of the
drug's effects over time (American Academy of Pain Medicine,
American Pain Society and American Society of Addiction Medicine
consensus document, 2001). Physical dependence is a state of
adaptation manifested by a drug class-specific withdrawal syndrome
produced by abrupt cessation, rapid dose reduction, decreasing blood
level of the drug, and/or administration of an antagonist (ibid).

The presence of tolerance or physical dependence does not
determine whether a drug has abuse potential, in the absence of
other abuse indicators such as rewarding properties. Many
medications that are not associated with abuse or addiction, such as
antidepressants, beta-blockers, and centrally acting
antihypertensive drugs, can produce physical dependence and
withdrawal symptoms after chronic use.

Tolerance to the subjective and performance effects of marijuana
has not been demonstrated in studies with humans. For example,
reaction times are not altered by acute administration of marijuana
in long term marijuana users (Block and Wittenborn, 1985). This may
be related to recent electrophysiological data showing that the
ability of delta\9\-THC to increase neuronal firing in the ventral
tegmental area (a region known to play a critical role in drug
reinforcement and reward) is not reduced following chronic
administration of the drug (Wu and French, 2000). On the other hand,
tolerance can develop in humans to marijuana-induced cardiovascular
and autonomic changes, decreased intraocular pressure, and sleep
alterations (Jones et al., 1981). Down-regulation of cannabinoid
receptors has been suggested as the mechanism underlying tolerance
to the effects of marijuana (Rodriguez de Fonseca et al., 1994;
Oviedo et al., 1993).

Acute administration of marijuana containing 2.1 percent
delta\9\-THC does not produce "hangover effects" (Chait et al.,
1985). In chronic marijuana users, though, a marijuana withdrawal
syndrome has been described that consists of restlessness,
irritability, mild agitation, insomnia, sleep EEG disturbances,
nausea, and cramping that resolves within a few days (Haney et al.,
1999). However, the American Psychiatric Association's Diagnostic
and Statistical Manual (DSM-IV-TR, 2000) does not include a listing
for cannabis withdrawal syndrome because, "symptoms of cannabis
withdrawal . . . have been described . . . but their clinical
significance is uncertain." A review of all current clinical
studies on cannabis withdrawal led to the recommendation by Budney
et al. (2004) that the DSM introduce a listing for cannabis
withdrawal that includes such symptoms as sleep difficulties,
strange dreams, decreased appetite, decreased weight, anger,
irritability, and anxiety. Based on clinical descriptions, this
syndrome appears to be mild compared to classical alcohol and
barbiturate withdrawal syndromes, which can include more serious
symptoms such as agitation, paranoia, and seizures. A recent study
comparing marijuana and tobacco withdrawal symptoms in humans
demonstrated that the magnitude and timecourse of the two withdrawal
syndromes are similar (Vandrey et al., 2005).

The production of an overt withdrawal syndrome in animals
following chronic delta\9\-THC administration has been variably
demonstrated under conditions of natural discontinuation. This may
be the result of the slow release of cannabinoids from adipose
storage, as well as the presence of the major psychoactive
metabolite, 11-hydroxy-delta\9\-THC. When investigators have shown
such a withdrawal syndrome in monkeys following the termination of
cannabinoid administration, the behaviors included transient
aggression, anorexia, biting, irritability, scratching, and yawning
(Budney et al., 2004). However, in rodents treated with a
cannabinoid antagonist following subacute administration of
delta\9\-THC, pronounced withdrawal symptoms, including wet dog
shakes, can be provoked (Breivogel et al., 2003).

Behavioral Sensitization

Sensitization to the effects of drugs is the opposite of
tolerance: instead of a reduction in behavioral response upon
repeated drug administration, animals that are sensitized
demonstrate an increase in behavioral response. Cadoni et al. (2001)
demonstrated that repeated exposure to delta\9\-THC can induce
sensitization to a variety of cannabinoids. These same animals also
have a sensitized response to administration of opioids, an effect
known as cross-sensitization. Conversely, when animals were
sensitized to the effects of morphine, there was cross-sensitization
to cannabinoids. Thus, the cannabinoid and opioids systems appear to
operate symmetrically in terms of cross-sensitization.

The impaired circulatory responses following delta\9\-THC
administration to standing, exercise, Valsalva maneuver, and cold
pressor testing suggest that cannabinoids induce a state of
sympathetic insufficiency. In humans, tolerance can develop to the
orthostatic hypotension (Jones, 2002; Sidney, 2002), possibly
related to plasma volume expansion, but does not develop to the
supine hypotensive effects (Benowitz and Jones, 1975). During
chronic marijuana ingestion, nearly complete tolerance develops to
tachycardia and psychological effects when subjects are challenged
with smoked marijuana. Electrocardiographic changes are minimal even
after large cumulative doses of delta\9\-THC. (Benowitz and Jones,
1975).

It is notable that marijuana smoking by older patients,
particularly those with some degree of coronary artery or
cerebrovascular disease, poses risks related to increased cardiac
work, increased catecholamines, carboxyhemoglobin, and postural
hypotension (Benowitz and Jones, 1981; Hollister, 1988).

Respiratory Effects

Transient bronchodilation is the most typical effect following
acute exposure to marijuana (Gong et al., 1984). Long-term use of
marijuana can lead to an increased frequency of chronic bronchitis
and pharyngitis, as well as chronic cough and increased sputum.
Pulmonary function tests reveal that large-airway obstruction can
occur with chronic marijuana smoking, as can cellular inflammatory
histopathological abnormalities in bronchial epithelium (Adams and
Martin, 1996; Hollister, 1986).

The evidence that marijuana may lead to cancer associated with
respiratory effects is inconsistent, with some studies suggesting a
positive correlation while others do not (Tashkin, 2005). Several
cases of lung cancer have been reported in young marijuana users
with no history of tobacco smoking or other significant risk factors
(Fung et al., 1999). Marijuana use may dose-dependently interact
with mutagenic sensitivity, cigarette smoking and alcohol use to
increase the risk of head and neck cancer (Zhang et al., 1999).
However, in the largest study to date with 1,650 subjects, no
positive association was found between marijuana use and lung cancer
(Tashkin et al., 2006). This finding held true regardless of extent
of marijuana use, when tobacco use and other potential confounding
factors were controlled.

The lack of evidence for carcinogenicity related to cannabis may
be related to the fact that intoxication from marijuana does not
require large amounts of smoked material.

[[Page 40558]]

This may be especially pertinent since marijuana is reportedly more
potent today than a generation ago. Thus, individuals may consume
much less marijuana than in previous decades to reach the desired
subjective effects, exposing them to less potential carcinogens.

Endocrine System

The presence of in vitro delta\9\-THC reduces binding of the
corticosteroid, dexamethasone, in hippocampal tissue from
adrenalectomized rats, suggesting an interaction with the
glucocorticoid receptor (Eldridge et al., 1991). Acute delta\9\-THC
releases corticosterone, but tolerance develops to this effect with
chronic administration (Eldridge et al., 1991).

Experimental administration of marijuana to humans does not
consistently alter endocrine parameters. In an early study, male
subjects who experimentally received smoked marijuana showed a
significant depression in luteinizing hormone and a significant
increase in cortisol were observed (Cone et al., 1986). However, two
later studies showed no changes in hormones. Male subjects who were
experimentally exposed to smoked delta\9\-THC (18 mg/marijuana
cigarette) or oral delta\9\-THC (10 mg t.i.d. for 3 days and on the
morning of the fourth day) showed no changes in plasma prolactin,
ACTH, cortisol, luteinizing hormone, or testosterone levels (Dax et
al., 1989). Similarly, a study with 93 men and 56 women showed that
chronic marijuana use did not significantly alter concentrations of
testosterone, luteinizing hormone, follicle stimulating hormone,
prolactin, or cortisol (Block et al., 1991).

Relatively little research has been performed on the effects of
experimentally administered marijuana on female reproductive system
functioning. In monkeys, delta\9\-THC administration suppressed
ovulation (Asch et al., 1981) and reduced progesterone levels
(Almirez et al., 1983). However, when women were studied following
experimental exposure to smoked marijuana, no hormonal or menstrual
cycle changes were observed (Mendelson and Mello, 1984). Brown and
Dobs (2002) suggest that the discrepancy between animal and human
hormonal response to cannabinoids may be attributed to the
development of tolerance in humans.

Recent data suggest that cannabinoid agonists may have
therapeutic value in the treatment of prostate cancer, a type of
carcinoma in which growth is stimulated by androgens. Research with
prostate cancer cells shows that the mixed CB1/
CB2 agonist, WIN-55212-2, induces apoptosis in prostate
cancer cell growth, as well as decreases in expression of androgen
receptors and prostate-specific antigens (Sarfaraz et al., 2005).

Immune System

Immune functions are altered by cannabinoids, but there can be
differences between the effects of synthetic, natural, and
endogenous cannabinoids, often in an apparently biphasic manner
depending on dose (Croxford and Yamamura, 2005).

Abrams et al. (2003) investigated the effect of marijuana on
immunological functioning in 62 AIDS patients who were taking
protease inhibitors. Subjects received one of the following three
times a day: smoked marijuana cigarette containing 3.95 percent
delta\9\-THC; oral tablet containing delta\9\-THC (2.5 mg oral
dronabinol); or oral placebo. There were no changes in CD4+ and CD8+
cell counts or HIV RNA levels or protease inhibitor levels between
groups, demonstrating no short-term adverse virologic effects from
using cannabinoids in individuals with compromised immune systems.

3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE DRUG OR
OTHER SUBSTANCE

The third factor the Secretary must consider is the state of
current scientific knowledge regarding marijuana. Thus, this section
discusses the chemistry, human pharmacokinetics, and medical uses of
marijuana.

Chemistry

According to the DEA, Cannabis sativa is the primary species of
cannabis currently marketed illegally in the United States of
America. From this plant, three derivatives are sold as separate
illicit drug products: marijuana, hashish, and hashish oil.

Each of these derivatives contains a complex mixture of
chemicals. Among the components are the 21 carbon terpenes found in
the plant as well as their carboxylic acids, analogues, and
transformation products known as cannabinoids (Agurell et al., 1984
and 1986; Mechoulam, 1973). The cannabinoids appear to naturally
occur only in the marijuana plant and most of the botanically-
derived cannabinoids have been identified. Among the cannabinoids,
delta\9\-THC (alternate name delta\1\-THC) and delta-8-
tetrahydrocannabinol (delta\8\-THC, alternate name delta\6\-THC) are
both found in marijuana and are able to produce the characteristic
psychoactive effects of marijuana. Because delta\9\-THC is more
abundant than delta\8\-THC, the activity of marijuana is largely
attributed to the former. Delta\8\-THC is found only in few
varieties of the plant (Hively et al., 1966).

Delta\9\-THC is an optically active resinous substance,
insoluble in water, and extremely lipid soluble. Chemically
delta\9\-THC is (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-
pentyl-6H-dibenzo-[b,d]pyran-1-ol or (-)-delta\9\-(trans)-
tetrahydrocannabinol. The (-)-trans isomer of delta\9\-THC is
pharmacologically 6 to 100 times more potent than the (+)-trans
isomer (Dewey et al., 1984).

Other cannabinoids, such as cannabidiol (CBD) and cannabinol
(CBN), have been characterized. CBD is not considered to have
cannabinol-like psychoactivity, but is thought to have significant
anticonvulsant, sedative, and anxiolytic activity (Adams and Martin,
1996; Agurell et al., 1984 and 1986; Hollister, 1986).

Marijuana is a mixture of the dried flowering tops and leaves
from the plant and is variable in content and potency (Agurell et
al., 1984 and 1986; Graham, 1976; Mechoulam, 1973). Marijuana is
usually smoked in the form of rolled cigarettes while hashish and
hash oil are smoked in pipes. Potency of marijuana, as indicated by
cannabinoid content, has been reported to average from as low as 1
to 2 percent to as high as 17 percent.

The concentration of delta\9\-THC and other cannabinoids in
marijuana varies with growing conditions and processing after
harvest. Other variables that can influence the strength, quality,
and purity of marijuana are genetic differences among the cannabis
plant species and which parts of the plant are collected (flowers,
leaves, stems, etc.) (Adams and Martin, 1996; Agurell et al., 1984;
Mechoulam, 1973). In the usual mixture of leaves and stems
distributed as marijuana, the concentration of delta\9\-THC ranges
widely from 0.3 to 4.0 percent by weight. However, specially grown
and selected marijuana can contain even 15 percent or greater
delta\9\-THC. Thus, a 1 gm marijuana cigarette might contain as
little as 3 mg or as much as 150 mg or more of delta\9\-THC.

Hashish consists of the cannabinoid-rich resinous material of
the cannabis plant, which is dried and compressed into a variety of
forms (balls, cakes, etc.). Pieces are then broken off, placed into
a pipe and smoked. DEA reports that cannabinoid content in hashish
averages 6 percent.

Hash oil is produced by solvent extraction of the cannabinoids
from plant material. Color and odor of the extract vary, depending
on the type of solvent used. Hash oil is a viscous brown or amber-
colored liquid that contains approximately 15 percent cannabinoids.
One or two drops of the liquid placed on a cigarette purportedly
produce the equivalent of a single marijuana cigarette (DEA, 2005).

The lack of a consistent concentration of delta\9\-THC in
botanical marijuana from diverse sources complicates the
interpretation of clinical data using marijuana. If marijuana is to
be investigated more widely for medical use, information and data
regarding the chemistry, manufacturing, and specifications of
marijuana must be developed.

Human Pharmacokinetics

Marijuana is generally smoked as a cigarette (weighing between
0.5 and 1.0 gm), or in a pipe. It can also be taken orally in foods
or as extracts of plant material in ethanol or other solvents.

The absorption, metabolism, and pharmacokinetic profile of
delta\9\-THC (and other cannabinoids) in marijuana or other drug
products containing delta\9\-THC vary with route of administration
and formulation (Adams and Martin, 1996; Agurell et al., 1984 and
1986). When marijuana is administered by smoking, delta\9\-THC in
the form of an aerosol is absorbed within seconds. The psychoactive
effects of marijuana occur immediately following absorption, with
mental and behavioral effects measurable up to 6 hours
(Grotenhermen, 2003; Hollister,

[[Page 40559]]

1986 and 1988). Delta\9\-THC is delivered to the brain rapidly and
efficiently as would be expected of a very lipid-soluble drug.

The bioavailability of the delta\9\-THC from marijuana in a
cigarette or pipe can range from 1 to 24 percent with the fraction
absorbed rarely exceeding 10 to 20 percent (Agurell et al., 1986;
Hollister, 1988). The relatively low and variable bioavailability
results from the following: significant loss of delta\9\-THC in
side-stream smoke, variation in individual smoking behaviors,
cannabinoid pyrolysis, incomplete absorption of inhaled smoke, and
metabolism in the lungs. A individual's experience and technique
with smoking marijuana is an important determinant of the dose that
is absorbed (Herning et al., 1986; Johansson et al., 1989).

After smoking, venous levels of delta\9\-THC decline
precipitously within minutes, and within an hour are about 5 to 10
percent of the peak level (Agurell et al., 1986; Huestis et al.,
1992a and 1992b). Plasma clearance of delta\9\-THC is approximately
950 ml/min or greater, thus approximating hepatic blood flow. The
rapid disappearance of delta\9\-THC from blood is largely due to
redistribution to other tissues in the body, rather than to
metabolism (Agurell et al., 1984 and 1986). Metabolism in most
tissues is relatively slow or absent. Slow release of delta\9\-THC
and other cannabinoids from tissues and subsequent metabolism
results in a long elimination half-life. The terminal half-life of
delta\9\-THC is estimated to range from approximately 20 hours to as
long as 10 to 13 days (Hunt and Jones, 1980), though reported
estimates vary as expected with any slowly cleared substance and the
use of assays of variable sensitivities. Lemberger et al. (1970)
determined the half-life of delta\9\-THC to range from 23 to 28
hours in heavy marijuana users to 60 to 70 hours in na[iuml]ve
users.

Characterization of the pharmacokinetics of delta\9\-THC and
other cannabinoids from smoked marijuana is difficult (Agurell et
al., 1986; Herning et al., 1986; Huestis et al., 1992a), in part
because a subject's smoking behavior during an experiment is
variable. Each puff delivers a discrete dose of delta\9\-THC. An
experienced marijuana smoker can titrate and regulate the dose to
obtain the desired acute psychological effects and to avoid overdose
and/or minimize undesired effects. For example, under naturalistic
conditions, users will hold marijuana smoke in the lungs for an
extended period of time, in order to prolong absorption and increase
psychoactive effects. The effect of experience in the psychological
response may explain why venous blood levels of delta\9\-THC
correlate poorly with intensity of effects and level of intoxication
(Agurell et al., 1986; Barnett et al., 1985; Huestis et al., 1992a).

Additionally, puff and inhalation volume changes with phase of
smoking, tending to be highest at the beginning and lowest at the
end of smoking a cigarette. Some studies found frequent users to
have higher puff volumes than less frequent marijuana users. During
smoking, as the cigarette length shortens, the concentration of
delta\9\-THC in the remaining marijuana increases; thus, each
successive puff contains an increasing concentration of delta\9\-
THC.

In contrast to smoking, the onset of effects after oral
administration of delta\9\-THC or marijuana is 30 to 90 min, which
peaks after 2 to 3 hours and continues for 4 to 12 hours
(Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984
and 1986). Oral bioavailability of delta\9\-THC, whether pure or in
marijuana, is low and extremely variable, ranging between 5 and 20
percent (Agurell et al., 1984 and 1986). Following oral
administration of radioactive-labeled delta\9\-THC, delta\9\-THC
plasma levels are low relative to those levels after smoking or
intravenous administration. There is inter- and intra-subject
variability, even when repeated dosing occurs under controlled
conditions. The low and variable oral bioavailability of delta\9\-
THC is a consequence of its first-pass hepatic elimination from
blood and erratic absorption from stomach and bowel. It is more
difficult for a user to titrate the oral delta\9\-THC dose than
marijuana smoking because of the delay in onset of effects after an
oral dose (typically 1 to 2 hours).

Cannabinoid metabolism is extensive. Delta\9\-THC is metabolized
via microsomal hydroxylation to both active and inactive metabolites
(Lemberger et al., 1970, 1972a, and 1972b; Agurell et al., 1986;
Hollister, 1988) of which the primary active metabolite was 11-
hydroxy-delta\9\-THC. This metabolite is approximately equipotent to
delta\9\-THC in producing marijuana-like subjective effects (Agurell
et al., 1986; Lemberger and Rubin, 1975). After oral administration,
metabolite levels may exceed that of delta\9\-THC and thus
contribute greatly to the pharmacological effects of oral delta\9\-
THC or marijuana. In addition to 11-hydroxy-delta\9\-THC, some
inactive carboxy metabolites have terminal half-lives of 50 hours to
6 days or more. The latter substances serve as long-term markers of
earlier marijuana use in urine tests. The majority of the absorbed
delta\9\-THC dose is eliminated in feces, and about 33 percent in
urine. Delta\9\-THC enters enterohepatic circulation and undergoes
hydroxylation and oxidation to 11-nor-9-carboxy-delta\9\-THC. The
glucuronide is excreted as the major urine metabolite along with
about 18 nonconjugated metabolites. Frequent and infrequent
marijuana users are similar in the way they metabolize delta\9\-THC
(Agurell et al., 1986).

Medical Uses for Marijuana

A NDA for marijuana/cannabis has not been submitted to the FDA
for any indication and thus no medicinal product containing
botanical cannabis has been approved for marketing. However, small
clinical studies published in the current medical literature
demonstrate that research with marijuana is being conducted in
humans in the United States under FDA-authorized investigational new
drug (IND) applications.

HHS states in a published guidance that it is committed to
providing "research-grade marijuana for studies that are the most
likely to yield usable, essential data" (HHS, 1999). The
opportunity for scientists to conduct clinical research with
botanical marijuana has increased due to changes in the process for
obtaining botanical marijuana from NIDA, the only legitimate source
of the drug for research in the United States. In May 1999, HHS
provided guidance on the procedures for providing research-grade
marijuana to scientists who intend to study marijuana in
scientifically valid investigations and well-controlled clinical
trials (DHHS, 1999). This action was prompted by the increasing
interest in determining whether cannabinoids have medical use
through scientifically valid investigations.

In February 1997, a National Institutes of Health (NIH)-
sponsored workshop analyzed available scientific information and
concluded that "in order to evaluate various hypotheses concerning
the potential utility of marijuana in various therapeutic areas,
more and better studies would be needed" (NIH, 1997). In addition,
in March 1999, the Institute of Medicine (IOM) issued a detailed
report that supported the need for evidence-based research into the
effects of marijuana and cannabinoid components of marijuana, for
patients with specific disease conditions. The IOM report also
emphasized that smoked marijuana is a crude drug delivery system
that exposes individuals to a significant number of harmful
substances and that "if there is any future for marijuana as a
medicine, it lies in its isolated components, the cannabinoids and
their synthetic derivatives." As such, the IOM recommended that
clinical trials should be conducted with the goal of developing safe
delivery systems (Institute of Medicine, 1999). Additionally, state-
level public initiatives, including referenda in support of the
medical use of marijuana, have generated interest in the medical
community for high quality clinical investigation and comprehensive
safety and effectiveness data.

For example, in 2000, the state of California established the
Center for Medicinal Cannabis Research (CMCR) (www.cmcr.ucsd.edu)
"in response to scientific evidence for therapeutic possibilities
of cannabis and local legislative initiatives in favor of
compassionate use" (Grant, 2005). State legislation establishing
the CMCR called for high quality medical research that will
"enhance understanding of the efficacy and adverse effects of
marijuana as a pharmacological agent," but stressed that the
project "should not be construed as encouraging or sanctioning the
social or recreational use of marijuana." CMCR has thus far funded
studies on the potential use of cannabinoids for the treatment of
multiple sclerosis, neuropathic pain, appetite suppression and
cachexia, and severe pain and nausea related to cancer or its
treatment by chemotherapy. To date, though, no NDAs utilizing
marijuana for these indications have been submitted to the FDA.

However, FDA approval of an NDA is not the sole means through
which a drug can be determined to have a "currently accepted
medical use" under the CSA. According to established case law, a
drug has a "currently accepted medical use" if all of the
following five elements have been satisfied:

Although the structures of many cannabinoids found in marijuana
have been characterized, a complete scientific analysis of all the
chemical components found in marijuana has not been conducted.
Safety studies for acute or subchronic administration of marijuana
have been carried out through a limited number of Phase 1 clinical
investigations approved by the FDA, but there have been no NDA-
quality studies that have scientifically assessed the efficacy and
full safety profile of marijuana for any medical condition. A
material conflict of opinion among experts precludes a finding that
marijuana has been accepted by qualified experts. At this time, it
is clear that there is not a consensus of medical opinion concerning
medical applications of marijuana. Finally, the scientific evidence
regarding the safety or efficacy of marijuana is typically available
only in summarized form, such as in a paper published in the medical
literature, rather than in a raw data format. As such, there is no
opportunity for adequate scientific scrutiny of whether the data
demonstrate safety or efficacy.

Alternately, a drug can be considered to have "a currently
accepted medical use with severe restrictions" (21 U.S.C.
812(b)(2)(B)), as allowed under the stipulations for a Schedule II
drug. However, as stated above, a material conflict of opinion among
experts precludes a finding that marijuana has been accepted by
qualified experts, even under conditions where its use is severely
restricted. Thus, to date, research on the medical use of marijuana
has not progressed to the point that marijuana can be considered to
have a "currently accepted medical use" or a "currently accepted
medical use with severe restrictions."

4. ITS HISTORY AND CURRENT PATTERN OF ABUSE

The fourth factor the Secretary must consider is the history and
current pattern of abuse of marijuana. A variety of sources provide
data necessary to assess abuse patterns and trends of marijuana. The
data indicators of marijuana use include NSDUH, Monitoring the
Future (MTF), DAWN, and Treatment Episode Data Set (TEDS), which are
described below:

National Survey on Drug Use and Health

The National Survey on Drug Use and Health (NSDUH, 2004; http://oas.samhsa.gov/nsduh.htm) is conducted annually by SAMHSA, an agency
of HHS. NSDUH provides estimates of the prevalence and incidence of
illicit drug, alcohol, and tobacco use in the United States. This
database was known until 2001 as the National Household Survey on
Drug Abuse. The survey is based on a nationally representative
sample of the civilian, non-institutionalized population 12 years of
age and older. The survey identifies whether an individual used a
drug during a certain period, but not the amount of the drug used on
each occasion. Excluded groups include homeless people, active
military personnel, and residents of institutions, such as jails.

According to the 2004 NSDUH, 19.1 million individuals (7.9
percent of the U.S. population) illicitly used drugs other than
alcohol and nicotine on a monthly basis, compared to 14.8 million
(6.7 percent of the U.S. population) users in 1999. This is an
increase from 1999 of 4.3 million (2.0 percent of the U.S.
population). The most frequently used illicit drug was marijuana,
with 14.6 million individuals (6.1 percent of the U.S. population)
using it monthly. Thus, regular illicit drug use, and more
specifically marijuana use, for rewarding responses is increasing.
The 2004 NSDUH estimated that 96.8 million individuals (40.2 percent
of the U.S. population) have tried marijuana at least once during
their lifetime. Thus, 15 percent of those who have tried marijuana
on one occasion go on to use it monthly, but 85 percent of them do
not.

Monitoring the Future

MTF (2005, http://www.monitoringthefuture.org) is a NIDA-
sponsored annual national survey that tracks drug use trends among
adolescents in the United States. The MTF surveys 8th, 10th, and
12th graders every spring in randomly selected U.S. schools. The MTF
survey has been conducted since 1975 for 12th graders and since 1991
for 8th and 10th graders by the Institute for Social Research at the
University of Michigan under a grant from NIDA. The 2005 sample
sizes were 17,300--8th graders; 16,700--10th graders; and 15,400--
12th graders. In all, a total of 49,300 students in 402 schools
participated.

Since 1999, illicit drug use among teens decreased and held
steady through 2005 in all three grades (Table 1). Marijuana
remained the most widely used illicit drug, though its use has
steadily decreased since 1999. For 2005, the annual prevalence rates
for marijuana use in grades 8, 10, and 12 were, respectively, 12.2
percent, 26.6 percent, and 33.6 percent. Current monthly prevalence
rates for marijuana use were 6.6 percent, 15.2 percent, and 19.8
percent. (See Table 1). According to Gruber and Pope (2002), when
adolescents who used marijuana reach their late 20's, the vast
majority of these individuals will have stopped using marijuana.

Table 1--Trends in Annual and Monthly Prevalence of Use of Various Drugs for Eighth, Tenth, and Twelfth Graders,
From Monitoring the Future. Percentages Represent Students in Survey Responding That They had Used a Drug Either
in the Past Year or in the Past 30 Days

SOURCE: The Monitoring the Future Study, the University of Michigan.
a. For 12th graders only, "any illicit drug" includes any use of marijuana, LSD, other hallucinogens, crack,
other cocaine, or heroin, or any use of other opiates, stimulants, barbiturates, or tranquilizers not under a
doctor's orders. For 8th and 10th graders, the use of other opiates and barbiturates was excluded.

Drug Abuse Warning Network

DAWN (2006, http://dawninfo.samhsa.gov/) is a national
probability survey of U.S. hospitals with EDs designed to obtain
information on ED visits in which recent drug use is implicated. The
ED data from a representative sample of hospital emergency
departments are weighted to produce national estimates. It is
critical to note that DAWN data and estimates for 2004 are not
comparable to those for any prior years because of vast

[[Page 40561]]

changes in the methodology used to collect the data. Further,
estimates for 2004 are the first to be based on a new, redesigned
sample of hospitals. Thus, the most recent estimates available are
for 2004.

Many factors can influence the estimates of ED visits, including
trends in the ED usage in general. Some drug users may have visited
EDs for a variety of reasons, some of which may have been life-
threatening, whereas others may have sought care at the ED for
detoxification because they needed certification before entering
treatment. DAWN data do not distinguish the drug responsible for the
ED visit from others used concomitantly. As stated in a recent DAWN
report, "Since marijuana/hashish is frequently present in
combination with other drugs, the reason for the ED contact may be
more relevant to the other drug(s) involved in the episode."

Marijuana was involved in 215,665 (CI: 175,930 to 255,400) ED
visits, while cocaine was involved in 383,350 (CI: 284,170 to
482,530) ED visits, heroin was involved in 162,137 (CI: 122,414 to
201,860) ED visits, and stimulants, including amphetamine and
methamphetamine, were involved in 102,843 (CI: 61,520 to 144,166) ED
visits. Other illicit drugs, such as PCP, MDMA, and GHB, were much
less frequently associated with ED visits.

Approximately 18 percent of ED visits involving marijuana were
for patients under the age of 18, whereas this age group accounts
for less than 1 percent of the ED visits involving heroin/morphine
and approximately 3 percent of the visits involving cocaine. Since
the size of the population differs across age groups, a measure
standardized for population size is useful to make comparisons. For
marijuana, the rates of ED visits per 100,000 population were
highest for patients aged 18 to 20 (225 ED visits per 100,000) and
for patients aged 21 to 24 (190 ED visits per 100,000).

Treatment Episode Data Set

TEDS (TEDS, 2003; http://oas.samhsa.gov/dasis.htm#teds2) system
is part of SAMHSA's Drug and Alcohol Services Information System
(Office of Applied Science, SAMHSA). TEDS comprises data on
treatment admissions that are routinely collected by States in
monitoring their substance abuse treatment systems. The TEDS report
provides information on the demographic and substance use
characteristics of the 1.8 million annual admissions to treatment
for abuse of alcohol and drugs in facilities that report to
individual State administrative data systems.

TEDS is an admission-based system, and TEDS admissions do not
represent individuals. Thus, a given individual admitted to
treatment twice within a given year would be counted as two
admissions. Additionally, TEDS does not include all admissions to
substance abuse treatment. TEDS includes facilities that are
licensed or certified by the States to provide substance abuse
treatment and that are required by the States to provide TEDS
client-level data. Facilities that report TEDS data are those that
receive State alcohol and/or drug agency funds for the provision of
alcohol and/or drug treatment services. The primary goal for TEDS is
to monitor the characteristics of treatment episodes for substance
abusers.

Primary marijuana abuse accounted for 15.5 percent of TEDS
admissions in 2003, the latest year for which data are available.
Three-quarters of the individuals admitted for marijuana were male
and 55 percent of the admitted individuals were white. The average
age at admission was 23 years. The largest proportion (84 percent)
of admissions to ambulatory treatment was for primary marijuana
abuse. More than half (57 percent) of marijuana treatment admissions
were referred through the criminal justice system.

Between 1993 and 2003, the percentage of admissions for primary
marijuana use increased from 6.9 percent to 15.5 percent, comparable
to the increase for primary opioid use from 13 percent in 1993 to
17.6 percent in 2003. In contrast, the percentage of admissions for
primary cocaine use declined from 12.6 percent in 1993 to 9.8
percent in 2003, and for primary alcohol use from 56.9 percent in
1993 to 41.7 percent in 2003.

Twenty-six percent of those individuals who were admitted for
primary use of marijuana reported its daily use, although 34.6
percent did not use marijuana in the past month. Nearly all (96.2
percent) of primary marijuana users utilized the drug by smoking it.
Over 90 percent of primary marijuana admissions used marijuana for
the first time before the age of 18.

5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

The fifth factor the Secretary must consider is the scope,
duration, and significance of marijuana abuse. According to 2004
data from NSDUH and MTF, marijuana remains the most extensively used
illegal drug in the United States, with 40.6 percent of U.S.
individuals over age 12 (96.6 million) and 44.8 percent of 12th
graders having used marijuana at least once in their lifetime. While
the majority of individuals over age 12 (85 percent) who have used
marijuana do not use the drug monthly, 14.6 million individuals (6.1
percent of the U.S. population) report that they used marijuana
within the past 30 days. An examination of use among various age
cohorts in NSDUH demonstrates that monthly use occurs primarily
among college age individuals, with use dropping off sharply after
age 25.

DAWN data show that marijuana was involved in 79,663 ED visits,
which amounts to 13 percent of all drug-related ED visits. Minors
accounted for 15 percent of these marijuana-related visits, making
marijuana the drug most frequently associated with ED visits for
individuals under the age of 18 years.

Data from TEDS show that 15.5 percent of all admissions were for
primary marijuana abuse. Approximately 90 percent of these primary
marijuana admissions were for individuals under the age of 18 years.

6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC

The sixth factor the Secretary must consider is the risk
marijuana poses to the public health. The risk to the public health
as measured by emergency room episodes, marijuana-related deaths,
and drug treatment admissions is discussed in full under Factors 1,
4, and 5, above. Accordingly, Factor 6 focuses on the health risks
to the individual user.

All drugs, both medicinal and illicit, have a broad range of
effects on the individual user that are dependent on dose and
duration of use among others. FDA-approved drug products can produce
adverse events (or "side effects") in some individuals even at
doses in the therapeutic range. When determining whether a drug
product is safe and effective for any indication, FDA performs an
extensive risk-benefit analysis to determine whether the risks posed
by the drug product's potential or actual side effects are
outweighed by the drug product's potential benefits. As marijuana is
not FDA-approved for any medicinal use, any potential benefits
attributed to marijuana use have not been found to be outweighed by
the risks. However, cannabinoids are generally potent psychoactive
substances and are pharmacologically active on multiple organ
systems.

The discussion of marijuana's central nervous system, cognitive,
cardiovascular, autonomic, respiratory, and immune system effects
are fully discussed under Factor 2. Consequences of marijuana use
and abuse are discussed below in terms of the risk from acute and
chronic use of the drug to the individual user (Institute of
Medicine, 1999).

Risks from acute use of marijuana

Acute use of marijuana impairs psychomotor performance,
including performance of complex tasks, which makes it inadvisable
to operate motor vehicles or heavy equipment after using marijuana
(Ramaekers et al., 2004). Dysphoria and psychological distress,
including prolonged anxiety reactions, are potential responses in a
minority of individuals who use marijuana (Haney et al., 1999).

Risks from chronic use of marijuana

Chronic exposure to marijuana smoke is considered to be
comparable to tobacco smoke with respect to increased risk of
cancer, lung damage, and poor pregnancy outcome. Although a
distinctive marijuana withdrawal syndrome has been identified,
indicating that marijuana produces physical dependence, this
phenomenon is mild and short-lived (Budney et al., 2004), as
described above under Factor 2.

The Diagnostic and Statistical Manual (DSM-IV-TR, 2000) of the
American Psychiatric Association states that the

[[Page 40562]]

consequences of cannabis abuse are as follows:

[P]eriodic cannabis use and intoxication can interfere with
performance at work or school and may be physically hazardous in
situations such as driving a car. Legal problems may occur as a
consequence of arrests for cannabis possession. There may be
arguments with spouses or parents over the possession of cannabis in
the home or its use in the presence of children. When psychological
or physical problems are associated with cannabis in the context of
compulsive use, a diagnosis of Cannabis Dependence, rather than
Cannabis Abuse, should be considered.

Individuals with Cannabis Dependence have compulsive use and
associated problems. Tolerance to most of the effects of cannabis
has been reported in individuals who use cannabis chronically. There
have also been some reports of withdrawal symptoms, but their
clinical significance is uncertain. There is some evidence that a
majority of chronic users of cannabinoids report histories of
tolerance or withdrawal and that these individuals evidence more
severe drug-related problems overall. Individuals with Cannabis
Dependence may use very potent cannabis throughout the day over a
period of months or years, and they may spend several hours a day
acquiring and using the substance. This often interferes with
family, school, work, or recreational activities. Individuals with
Cannabis Dependence may also persist in their use despite knowledge
of physical problems (e.g., chronic cough related to smoking) or
psychological problems (e.g., excessive sedation and a decrease in
goal-oriented activities resulting from repeated use of high doses).

7. ITS PSYCHIC OR PHYSIOLOGIC DEPENDENCE LIABILITY

The seventh factor the Secretary must consider is marijuana's
psychic or physiologic dependence liability. Physical dependence is
a state of adaptation manifested by a drug class-specific withdrawal
syndrome produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug, and/or administration of an
antagonist (American Academy of Pain Medicine, American Pain Society
and American Society of Addiction Medicine consensus document,
2001). Long-term, regular use of marijuana can lead to physical
dependence and withdrawal following discontinuation as well as
psychic addiction or dependence. The marijuana withdrawal syndrome
consists of symptoms such as restlessness, mild agitation, insomnia,
nausea, and cramping that may resolve after 4 days, and may require
in-hospital treatment. It is distinct from the withdrawal syndromes
associated with alcohol and heroin use (Budney et al., 1999; Haney
et al., 1999). Lane and Phillips-Bute (1998) describes milder cases
of dependence including symptoms that are comparable to those from
caffeine withdrawal, including decreased vigor, increased fatigue,
sleepiness, headache, and reduced ability to work. The marijuana
withdrawal syndrome has been reported in adolescents who were
admitted for substance abuse treatment or in individuals who had
been given marijuana on a daily basis during research conditions.
Withdrawal symptoms can also be induced in animals following
administration of a cannabinoid antagonist after chronic delta\9\-
THC administration (Breivogel et al., 2003).

Tolerance is a state of adaptation in which exposure to a drug
induces changes that result in a diminution of one or more of the
drug's effects over time (American Academy of Pain Medicine,
American Pain Society and American Society of Addiction Medicine
consensus document, 2001). Tolerance can develop to marijuana-
induced cardiovascular and autonomic changes, decreased intraocular
pressure, sleep and sleep EEG, and mood and behavioral changes
(Jones et al., 1981). Down-regulation of cannabinoid receptors has
been suggested as the mechanism underlying tolerance to the effects
of marijuana (Rodriguez de Fonseca et al., 1994). Pharmacological
tolerance does not indicate the physical dependence liability of a
drug.

8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE
ALREADY CONTROLLED UNDER THIS ARTICLE

The eighth factor the Secretary must consider is whether
marijuana is an immediate precursor of a controlled substance.
Marijuana is not an immediate precursor of another controlled
substance.

RECOMMENDATION

After consideration of the eight factors discussed above, HHS
recommends that marijuana remain in Schedule I of the CSA. Marijuana
meets the three criteria for placing a substance in Schedule I of
the CSA under 21 U.S.C. 812(b)(1):

1) Marijuana has a high potential for abuse:

The large number of individuals using marijuana on a regular
basis, its widespread use, and the vast amount of marijuana that is
available for illicit use are indicative of the high abuse potential
for marijuana. Approximately 14.6 million individuals in the United
States (6.1 percent of the U.S. population) used marijuana monthly
in 2003. A 2003 survey indicates that by 12th grade, 33.6 percent of
students report having used marijuana in the past year, and 19.8
percent report using it monthly. In Q3 to Q4 2003, 79,663 ED visits
were marijuana-related, representing 13 percent of all drug-related
episodes. Primary marijuana use accounted for 15.5 percent of
admissions to drug treatment programs in 2003. Marijuana has dose-
dependent reinforcing effects, as demonstrated by data that humans
prefer higher doses of marijuana to lower doses. In addition, there
is evidence that marijuana use can result in psychological
dependence in at risk individuals.

2) Marijuana has no currently accepted medical use in treatment in the
United States:

The FDA has not yet approved an NDA for marijuana. The
opportunity for scientists to conduct clinical research with
marijuana exists under the HHS policy supporting clinical research
with botanical marijuana. While there are INDs for marijuana active
at the FDA, marijuana does not have a currently accepted medical use
for treatment in the United States, nor does it have an accepted
medical use with severe restrictions.

A drug has a "currently accepted medical use" if all of the
following five elements have been satisfied:

Although the structures of many cannabinoids found in marijuana
have been characterized, a complete scientific analysis of all the
chemical components found in marijuana has not been conducted.
Safety studies for acute or subchronic administration of marijuana
have been carried out through a limited number of Phase 1 clinical
investigations approved by the FDA, but there have been no NDA-
quality studies that have scientifically assessed the efficacy of
marijuana for any medical condition. A material conflict of opinion
among experts precludes a finding that marijuana has been accepted
by qualified experts. At this time, it is clear that there is not a
consensus of medical opinion concerning medical applications of
marijuana. Finally, the scientific evidence regarding the safety or
efficacy of marijuana is typically available only in summarized
form, such as in a paper published in the medical literature, rather
than in a raw data format. As such, there is no opportunity for
adequate scientific scrutiny of whether the data demonstrate safety
or efficacy.

Alternately, a drug can be considered to have "a currently
accepted medical use with severe restrictions" (21 U.S.C.
812(b)(2)(B)), as allowed under the stipulations for a Schedule II
drug. However, as stated above, a material conflict of opinion among
experts precludes a finding that marijuana has been accepted by
qualified experts, even under conditions where its use is severely
restricted. To date, research on the medical use of marijuana has
not progressed to the point that marijuana can be considered to have
a "currently accepted medical use" or a "currently accepted
medical use with severe restrictions."

3) There is a lack of accepted safety for use of marijuana under
medical supervision.

At present, there are no FDA-approved marijuana products, nor is
marijuana under NDA evaluation at the FDA for any indication.
Marijuana does not have a currently accepted medical use in
treatment in the United States or a currently accepted medical use
with severe restrictions. The Center for Medicinal Cannabis Research
in California, among others, is conducting research with marijuana
at the IND level, but these studies have not yet progressed to the
stage of submitting an NDA. Thus, at this time, the known risks of
marijuana use have

[[Page 40563]]

not been shown to be outweighed by specific benefits in well-
controlled clinical trials that scientifically evaluate safety and
efficacy.

In addition, the agency cannot conclude that marijuana has an
acceptable level of safety without assurance of a consistent and
predictable potency and without proof that the substance is free of
contamination. If marijuana is to be investigated more widely for
medical use, information and data regarding the chemistry,
manufacturing, and specifications of marijuana must be developed.
Therefore, HHS concludes that, even under medical supervision,
marijuana has not been shown at present to have an acceptable level
of safety.

Community Epidemiology Work Group, National Institutes of Health,
National Institute on Drug Abuse, Epidemiologic Trends in Drug
Abuse, Volume I: Highlights and Executive Summary, June 2000, http://www.nida.nih.gov/CEWG/pubs.html.

Department of Health and Human Services. Announcement of the
Department of Health and Human Services Guidance on Procedures for
the Provision of Marijuana for Medical Research. May 21, 1999.
(http://grants.nih.gov/grants/guide/notice-files/not99-091.html).

Institute of Medicine. Division of Health Sciences Policy. Marijuana
and Health: Report of a Study by a Committee of the Institute of
Medicine, Division of Health Sciences Policy. Washington, DC:
National Academy Press, 1982.

On October 9, 2002, the Coalition for Rescheduling Cannabis
submitted a petition to the Drug Enforcement Administration (DEA) to
initiate proceedings for a repeal of the rules or regulations that
place marijuana \3\ in schedule I of the Controlled Substances Act
(CSA). The petition requests that marijuana be rescheduled as
"cannabis" in either schedule III, IV, or V of the CSA. The
petitioner claims that:

All parts of the plant Cannabis sativa L., whether growing or
not; the seeds thereof; the resin extracted from any part of such
plant; and every compound, manufacture, salt, derivative, mixture,
or preparation of such plant, its seeds or resin. Such term does not
include the mature stalks of such plant, fiber produced from such
stalks, oil or cake made from the seeds of such plant, any other
compound, manufacture, salt, derivative, mixture, or preparation of
such mature stalks (except the resin extracted there from), fiber,
oil, or cake, or the sterilized seed of such plant which is
incapable of germination. 21 U.S.C. 802(16).

Note that "marihuana" is the spelling originally used in the
CSA. This document uses the spelling that is more common in current
usage, "marijuana."

3. Cannabis has an abuse potential lower than schedule I or II
drugs; and

4. Cannabis has a dependence liability that is lower than
schedule I or II drugs.

The DEA accepted this petition for filing on April 3, 2003. In
accordance with 21 U.S.C. 811(b), after gathering the necessary
data, the DEA requested a medical and scientific evaluation and
scheduling recommendation for cannabis from the Department of Health
and Human Services (DHHS) on July 12, 2004. On December 6, 2006, the
DHHS provided its scientific and medical evaluation titled Basis for
the Recommendation for Maintaining Marijuana in Schedule I of the
Controlled Substances Act and recommended that marijuana continue to
be controlled in schedule I of the CSA.

The CSA requires DEA to determine whether the DHHS scientific
and medical evaluation and scheduling recommendation and "all other
relevant data" constitute substantial evidence that the drug should
be rescheduled as proposed in the petition. 21 U.S.C. 811(b). This
document is prepared accordingly.

The Attorney General "may by rule" transfer a drug or other
substance between schedules if he finds that such drug or other
substance has a potential for abuse, and makes with respect to such
drug or other substance the findings prescribed by subsection (b) of Section 812 for the schedule in which such drug is to be placed. 21
U.S.C. 811(a)(1). In order for a substance to be placed in schedule
I, the Attorney General must find that:

A. The drug or other substance has a high potential for abuse.

B. The drug or other substance has no currently accepted medical
use in treatment in the United States.

C. There is a lack of accepted safety for use of the drug or
other substance under medical supervision.

21 U.S.C. 812(b)(1)(A)-(C). To be classified in one of the other
schedules (II through V), a drug of abuse must have either a
"currently accepted medical use in treatment in the United States
or a currently accepted medical use with severe restrictions." 21
U.S.C. 812(b)(2)-(5). If a controlled substance has no such
currently accepted medical use, it must be placed in schedule I. See
Notice of Denial of Petition, 66 FR 20038, 20038 (Apr. 18, 2001)
("Congress established only one schedule--schedule I--for drugs of
abuse with 'no currently accepted medical use in treatment in the
United States' and 'lack of accepted safety for use . . . under
medical supervision.'").

In deciding whether to grant a petition to initiate rulemaking
proceedings with respect to a particular drug, DEA must determine
whether there is sufficient evidence to conclude that the drug meets
the criteria for placement in another schedule based on the criteria
set forth in 21 U.S.C. 812(b). To do so, the CSA requires that DEA
and DHHS consider eight factors as specified in 21 U.S.C. 811(c).
This document is organized according to these eight factors.

With specific regard to the issue of whether the drug has a
currently accepted medical use in treatment in the United States,
DHHS states that the FDA has not evaluated nor approved a new drug
application (NDA) for marijuana. The long-established factors
applied by the DEA for determining whether a drug has a "currently
accepted medical use" under the CSA are:

[[Page 40567]]

1. The drug's chemistry must be known and reproducible;

2. There must be adequate safety studies;

3. There must be adequate and well-controlled studies proving
efficacy;

4. The drug must be accepted by qualified experts; and

5. The scientific evidence must be widely available.

57 FR 10,499, 10,506 (1992); Alliance for Cannabis Therapeutics v.
DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994) (ACT) (upholding these
factors as valid criteria for determining "accepted medical use").
A drug will be deemed to have a currently accepted medical use for
CSA purposes only if all five of the foregoing elements are
demonstrated. This test is considered here under the third factor.

1. Actual or relative potential for abuse. Marijuana has a high
abuse potential. It is the most widely used illicit substance in the
United States. Preclinical and clinical data show that it has
reinforcing effects characteristic of drugs of abuse. National
databases on actual abuse show marijuana is the most widely abused
drug, including significant numbers of substance abuse treatment
admissions. Data on marijuana seizures show widespread availability
and trafficking.

2. Scientific evidence of its pharmacological effect. The
scientific understanding of marijuana, cannabinoid receptors, and
the endocannabinoid system has improved. Marijuana produces various
pharmacological effects, including subjective (e.g., euphoria,
dizziness, disinhibition), cardiovascular, acute and chronic
respiratory, immune system, cognitive impairment, and prenatal
exposure effects as well as possible increased risk of schizophrenia
among those predisposed to psychosis.

3. Current scientific knowledge. There is no currently accepted
medical use for marijuana in the United States. Under the five-part
test for currently accepted medical use approved in ACT, 15 F.3d at
1135, there is no complete scientific analysis of marijuana's
chemical components; there are no adequate safety studies; there are
no adequate and well-controlled efficacy studies; there is not a
consensus of medical opinion concerning medical applications of
marijuana; and the scientific evidence regarding marijuana's safety
and efficacy is not widely available. While a number of states have
passed voter referenda or legislative actions authorizing the use of
marijuana for medical purposes, this does not establish a currently
accepted medical use under federal law. To date, scientific and
medical research has not progressed to the point that marijuana has
a currently accepted medical use, even under conditions where its
use is severely restricted.

4. History and current pattern of abuse. Marijuana use has been
relatively stable from 2002 to 2009, and it continues to be the most
widely used illicit drug. In 2009, there were 16.7 million current
users. There were also 2.4 million new users, most of whom were less
than 18 years of age. During the same period, marijuana was the most
frequently identified drug exhibit in federal, state, and local
laboratories. High consumption of marijuana is fueled by increasing
amounts of both domestically grown and illegally smuggled foreign
source marijuana, and an increasing percentage of seizures involve
high potency marijuana.

5. Scope, duration, and significance of abuse. Abuse of
marijuana is widespread and significant. In 2008, for example, an
estimated 3.9 million people aged 12 or older used marijuana on a
daily or almost daily basis over a 12-month period. In addition, a
significant proportion of all admissions for treatment for substance
abuse are for primary marijuana abuse: in 2007, 16 percent of all
admissions were for primary marijuana abuse, representing 287,933
individuals. Of individuals under the age of 19 admitted to
substance abuse treatment, more than half were treated for primary
marijuana abuse.

6. Risk, if any, to public health. Together with the health
risks outlined in terms of pharmacological effects above, public
health risks from acute use of marijuana include impaired
psychomotor performance, including impaired driving, and impaired
performance on tests of learning and associative processes. Public
health risks from chronic use of marijuana include respiratory
effects, physical dependence, and psychological problems.

7. Psychic or physiological dependence liability. Long-term,
regular use of marijuana can lead to physical dependence and
withdrawal following discontinuation, as well as psychic addiction
or dependence.

8. Immediate precursor. Marijuana is not an immediate precursor
of any controlled substance.

This review shows, in particular, that the evidence is
insufficient with respect to the specific issue of whether marijuana
has a currently accepted medical use under the five-part test. The
evidence was insufficient in this regard on the prior two occasions
when DEA considered petitions to reschedule marijuana in 1992 (57 FR
10499) \4\ and in 2001 (66 FR 20038).\5\ Little has changed since
then with respect to the lack of clinical evidence necessary to
establish that marijuana has a currently accepted medical use: only
a limited number of FDA-approved Phase 1 clinical investigations
have been carried out, and there have been no studies that have
scientifically assessed the efficacy and full safety profile of
marijuana for any medical condition.\6\ The limited existing
clinical evidence is not adequate to warrant rescheduling of
marijuana under the CSA.

To the contrary, the data in this Scheduling Review document
show that marijuana continues to meet the criteria for schedule I
control under the CSA for the following reasons:

1. Marijuana has a high potential for abuse.

2. Marijuana has no currently accepted medical use in treatment
in the United States.

3. Marijuana lacks accepted safety for use under medical
supervision.

FACTOR 1: THE DRUG'S ACTUAL OR RELATIVE POTENTIAL FOR ABUSE

Marijuana is the most commonly abused illegal drug in the United
States. It is also the most commonly used illicit drug by American
high-schoolers. Marijuana is the most frequently identified drug in
state, local and federal forensic laboratories, with increasing
amounts both of domestically grown and of illicitly smuggled
marijuana. Marijuana's main psychoactive ingredient, [Delta]\9\-THC,
is an effective reinforcer in laboratory animals, including primates
and rodents. These animal studies both predict and support the
observations that [Delta]\9\-THC, whether smoked as marijuana or
administered by other routes, produces reinforcing effects in
humans. Such reinforcing effects can account for the repeated abuse
of marijuana.

A. Indicators of Abuse Potential

DHHS has concluded in its document, "Basis for the
Recommendation for Maintaining Marijuana in Schedule I of the
Controlled Substances Act", that marijuana has a high potential for
abuse. The finding of "abuse potential" is critical for control
under the Controlled Substances Act (CSA). Although the term is not
defined in the CSA, guidance in determining abuse potential is
provided in the legislative history of the Act (Comprehensive Drug
Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-144, 91st
Cong., Sess.1 (1970), reprinted in 1970 U.S.C.C.A.N. 4566, 4603).
Accordingly, the following items are indicators that a drug or other
substance has potential for abuse:

There is evidence that individuals are taking the drug
or other substance in amounts sufficient to create a hazard to their
health or to the safety of other individuals or to the community; or

There is significant diversion of the drug or other
substance from legitimate drug channels; or

Individuals are taking the drug or substance on their
own initiative rather than on the basis of medical advice from a
practitioner licensed by law to administer such drugs; or

The drug is a new drug so related in its action to a
drug or other substance already listed as having a potential for
abuse to make it likely that the drug substance will have the same
potential for abuse as such drugs, thus

[[Page 40568]]

making it reasonable to assume that there may be significant
diversion from legitimate channels, significant use contrary to or
without medical advice, or that it has a substantial capability of
creating hazards to the health of the user or to the safety of the
community. Of course, evidence of actual abuse of a substance is
indicative that a drug has a potential for abuse.

After considering the above items, DHHS has found that marijuana
has a high potential for abuse.

1. There is evidence that individuals are taking the drug or
other substance in amounts sufficient to create a hazard to their
health or to the safety of other individuals or to the community.

Marijuana is the most highly used illicit substance in the
United States. Smoked marijuana exerts a number of cardiovascular
and respiratory effects, both acutely and chronically and can cause
chronic bronchitis and inflammatory abnormalities of the lung
tissue. Marijuana's main psychoactive ingredient [Delta]\9\-THC
alters immune function and decreases resistance to microbial
infections. The cognitive impairments caused by marijuana use that
persist beyond behaviorally detectable intoxication may have
significant consequences on workplace performance and safety,
academic achievement, and automotive safety, and adolescents may be
particularly vulnerable to marijuana's cognitive effects. Prenatal
exposure to marijuana was linked to children's poorer performance in
a number of cognitive tests. Data on the extent and scope of
marijuana abuse are presented under factors 4 and 5 of this
analysis. DHHS's discussion of the harmful health effects of
marijuana and additional information gathered by DEA are presented
under factor 2, and the assessment of risk to the public health
posed by acute and chronic marijuana abuse is presented under factor
6 of this analysis.

2. There is significant diversion of the drug or other substance
from legitimate drug channels.

DHHS states that at present, marijuana is legally available
through legitimate channels for research only and thus has a limited
potential for diversion. (DEA notes that while a number of states
have passed voter referenda or legislative actions authorizing the
use of marijuana for medical purposes, this does not establish a
currently accepted medical use under federal law.) In addition, the
lack of significant diversion of investigational supplies may result
from the ready availability of illicit cannabis of equal or greater
quality.

DEA notes that the magnitude of the demand for illicit marijuana
is evidenced by information from a number of databases presented
under factor 4. Briefly, marijuana is the most commonly abused
illegal drug in the United States. It is also the most commonly used
illicit drug by American high-schoolers. Marijuana is the most
frequently identified drug in state, local, and federal forensic
laboratories, with increasing amounts both of domestically grown and
of illicitly smuggled marijuana. An observed increase in the potency
of seized marijuana also raises concerns.

3. Individuals are taking the drug or substance on their own
initiative rather than on the basis of medical advice from a
practitioner licensed by law to administer such drugs.

16.7 million adults over the age of 12 reported having used
marijuana in the past month, according to the 2009 National Survey
on Drug Use and Health (NSDUH), as further described later in this
factor. DHHS states in its 2006 analysis of the petition that the
FDA has not evaluated or approved a new drug application (NDA) for
marijuana for any therapeutic indication, although several
investigational new drug (IND) applications are currently active.
Based on the large number of individuals who use marijuana, DHHS
concludes that the majority of individuals using cannabis do so on
their own initiative, not on the basis of medical advice from a
practitioner licensed to administer the drug in the course of
professional practice.

4. The drug is a new drug so related in its action to a drug or
other substance already listed as having a potential for abuse to
make it likely that the drug substance will have the same potential
for abuse as such drugs, thus making it reasonable to assume that
there may be significant diversions from legitimate channels,
significant use contrary to or without medical advice, or that it
has a substantial capability of creating hazards to the health of
the user or to the safety of the community. Of course, evidence of
actual abuse of a substance is indicative that a drug has a
potential for abuse.

Marijuana is not a new drug. Marijuana's primary psychoactive
ingredient delta-9-tetrahydrocannabinol ([Delta]\9\-THC) is
controlled in schedule I of the CSA. DHHS states that there are two
drug products containing cannabinoid compounds that are structurally
related to the active components in marijuana. Both are controlled
under the CSA. Marinol is a schedule III drug product containing
synthetic [Delta]\9\-THC, known generically as dronabinol,
formulated in sesame oil in soft gelatin capsules. Marinol was
approved by the FDA in 1985 for the treatment of two medical
conditions: nausea and vomiting associated with cancer chemotherapy
in patients that had failed to respond adequately to conventional
anti-emetic treatments, and for the treatment of anorexia associated
with weight loss in patients with acquired immunodeficiency syndrome
(AIDS). Cesamet is a drug product containing the schedule II
substance, nabilone, that was approved for marketing by the FDA in
1985 for the treatment of nausea and vomiting associated with cancer
chemotherapy. All other structurally related cannabinoids in
marijuana are already listed as Schedule I drugs under the CSA.

In addition, DEA notes that marijuana and its active ingredient
[Delta]\9\-THC are related in their action to other controlled drugs
of abuse when tested in preclinical and clinical tests of abuse
potential. Data showing that marijuana and [Delta]\9\-THC exhibit
properties common to other controlled drugs of abuse in those tests
are described below in this factor.

In summary, examination of the indicators set forth in the
legislative history of the CSA demonstrates that marijuana has a
high potential for abuse. Indeed, marijuana is abused in amounts
sufficient to create hazards to public health and safety; there is
significant trafficking of the substance; individuals are using
marijuana on their own initiative, for the vast majority, rather
than on the basis of medical advice; and finally, marijuana exhibits
several properties common to those of drugs already listed as having
abuse potential.

The petitioner states that, "widespread use of cannabis is not
an indication of its abuse potential [...] ." (Exh. C, Section
IV(15), pg. 87).

To the contrary, according to the indicators set forth in the
legislative history of the CSA as described above, the fact that
"Individuals are taking the drug or substance on their own
initiative rather than on the basis of medical advice from a
practitioner licensed by law to administer such drugs" is indeed
one of several indicators that a drug has high potential for abuse.

B. Abuse Liability Studies

In addition to the indicators suggested by the CSA's legislative
history, data as to preclinical and clinical abuse liability
studies, as well as actual abuse, including clandestine manufacture,
trafficking, and diversion from legitimate sources, are considered
in this factor.

Abuse liability evaluations are obtained from studies in the
scientific and medical literature. There are many preclinical
measures of a drug's effects that when taken together provide an
accurate prediction of the human abuse liability. Clinical studies
of the subjective and reinforcing effects in humans and
epidemiological studies provide quantitative data on abuse liability
in humans and some indication of actual abuse trends. Both
preclinical and clinical studies have clearly demonstrated that
marijuana and [Delta]\9\-THC possess the attributes associated with
drugs of abuse: they function as a positive reinforcer to maintain
drug-seeking behavior, they function as a discriminative stimulus,
and they have dependence potential.

Preclinical and most clinical abuse liability studies have been
conducted with the psychoactive constituents of marijuana, primarily
[Delta]\9\-THC and its metabolite, 11-OH- [Delta]\9\-THC.
[Delta]\9\-THC's subjective effects are considered to be the basis
for marijuana's abuse liability. The following studies provide a
summary of that data.

1. Preclinical Studies

Delta-9-THC is an effective reinforcer in laboratory animals,
including primates and rodents, as these animals will self-
administer [Delta]\9\-THC. These animal studies both predict and
support the observations that [Delta]\9\-THC, whether smoked as
marijuana or administered by other routes, produces reinforcing
effects in humans. Such reinforcing effects can account for the
repeated abuse of marijuana.

a. Discriminative Stimulus Effects

The drug discrimination paradigm is used as an animal model of
human subjective effects (Solinas et al., 2006). This procedure
provides a direct measure of stimulus

[[Page 40569]]

specificity of a test drug in comparison with a known standard drug
or a neutral stimulus (e.g., injection of saline water). The light-
headedness and warmth associated with drinking alcohol or the
jitteriness and increased heart rate associated with drinking coffee
are examples of substance-specific stimulus effects. The drug
discrimination paradigm is based on the ability of nonhuman and
human subjects to learn to identify the presence or absence of these
stimuli and to differentiate among the constellation of stimuli
produced by different pharmacological classes. In drug
discrimination studies, the drug stimuli function as cues to guide
behavioral choice, which is subsequently reinforced with other
rewards. Repeated pairing of the reinforcer with only drug-
appropriate responses can engender reliable discrimination between
drug and no-drug or amongst several drugs. Because some
interoceptive stimuli are believed to be associated with the
reinforcing effects of drugs, the drug discrimination paradigm is
used to evaluate the abuse potential of new substances.

DHHS states that in the drug discrimination test, animals are
trained to respond by pressing one bar when they receive the known
drug of abuse and another bar when they receive placebo.

DEA notes several studies that show that the discriminative
stimulus effects of [Delta]\9\-THC are mediated via a cannabinoid
receptor, specifically, the CB1 receptor subtype, and
that the CB1 antagonist rimonabant (SR 141716A)
antagonizes the discriminative stimulus effects of [Delta]\9\-THC in
several species (P[eacute]rio et al., 1996; Mansbach et al., 1996;
J[auml]rbe et al., 2001). The subjective effects of marijuana and
[Delta]\9\-THC are, therefore, mediated by a neurotransmitter system
in the brain that is specific to [Delta]\9\-THC and cannabinoids.

b. Self-Administration Studies

Self-administration is a behavioral assay that measures the
rewarding effects of a drug that increase the likelihood of
continued drug-taking behavior. Drugs that are self-administered by
animals are likely to produce rewarding effects in humans. A strong
correlation exists between drugs and other substances that are
abused by humans and those that maintain self-injection in
laboratory animals (Schuster and Thompson, 1969; Griffiths et al.,
1980). As a result, intravenous self-injection of psychoactive
substances in laboratory animals is considered to be useful for the
prediction of human abuse liability of these compounds (Johanson and
Balster, 1978; Collins et al., 1984).

DHHS states that self-administration of hallucinogenic-like
drugs, such as cannabinoids, lysergic acid diethylamide (LSD), and
mescaline, has been difficult to demonstrate in animals (Yanagita,
1980). DHHS further states that an inability to establish self-
administration has no practical importance in the assessment of
abuse potential, because it is known that humans voluntarily consume
a particular drug (such as cannabis) for its pleasurable effects.

DHHS states that the experimental literature generally reports
that na[iuml]ve animals will not self-administer cannabinoids unless
they have had previous experience with other drugs of abuse,
however, animal research in the past decade has provided several
animal models of reinforcement by cannabinoids to allow for pre-
clinical research into cannabinoids' reinforcing effects. Squirrel
monkeys trained to self-administer intravenous cocaine will continue
to respond at the same rate as when [Delta]\9\-THC is substituted
for cocaine, at doses that are comparable to those used by humans
who smoke marijuana (Tanda et al., 2000). This effect is blocked by
the cannabinoid receptor antagonist, SR 141716. Squirrel monkeys
without a history of any drug exposure can be successfully trained
to self-administer [Delta]\9\-THC intravenously (Justinova et al.,
2003). The maximal rate of responding is 4 [micro]g/kg/injection,
which is 2-3 times greater than that observed in previous studies
using cocaine-experienced monkeys. Rats will self-administer
[Delta]\9\-THC when it is applied intracerebroventricularly
(i.c.v.), but only at the lowest doses tested (0.01:-0.02/[micro]g/
infusion) (Braida et al., 2004). This effect is antagonized by the
cannabinoid antagonist SR141716 and by the opioid antagonist
naloxone (Braida et al., 2004). Additionally, mice will self-
administer WIN 55212, a synthetic CB1 receptor agonist
with a non-cannabinoid structure (Martellotta et al., 1998).

DEA notes a study showing that the opioid antagonist naltrexone
reduces the self-administration responding for [Delta]\9\-THC in
squirrel monkeys (Justinova et al., 2004). These investigators,
using second-order schedules of drug-seeking procedures, also showed
that pre-session administration of [Delta]\9\-THC and other
cannabinoid agonists, or morphine, but not cocaine, reinstates the
[Delta]\9\-THC seeking behavior following a period of abstinence
(Justinova et al., 2008). Furthermore, the endogenous cannabinoid
anandamide and its synthetic analog methanandamide are self-
administered by squirrel monkeys, and CB1 receptor
antagonism blocks the reinforcing effect of both substances
(Justinova et al., 2005).

c. Place Conditioning Studies

Conditioned place preference (CPP) is another behavioral assay
used to determine if a drug has rewarding properties. In this test,
animals in a drug-free state are given the opportunity to spend time
in two distinct environments: one where they previously received a
drug and one where they received a placebo. If the drug is
reinforcing, animals in a drug-free state will choose to spend more
time in the environment paired with the drug when both environments
are presented simultaneously.

DHHS states that animals exhibit CPP to [Delta]\9\-THC, but only
at the lowest doses tested (0.075-0.75 mg/kg, i.p.) (Braida et al.,
2004). The effect is antagonized by the cannabinoid antagonist,
rimonabant, as well as the opioid antagonist, naloxone. The effect
of naloxone on CPP to [Delta]\9\-THC raises the possibility that the
opioid system may be involved in the rewarding properties of
[Delta]\9\-THC and marijuana. DEA notes a recent review (Murray and
Bevins, 2010) that further explores the currently available
knowledge on [Delta]\9\-THC's ability to induce CPP and conditioned
place aversion (CPA), and further supports that low doses of
[Delta]\9\-THC appear to have conditioned rewarding effects, whereas
higher doses have aversive effects.

2. Clinical Studies

DHHS states that the physiological, psychological, and
behavioral effects of marijuana vary among individuals and presents
a list of common responses to cannabinoids, as described in the
scientific literature (Adams and Martin, 1996; Hollister, 1986,
1988; Institute of Medicine, 1982):

5. Heightened imagination leading to a subjective sense of
increased creativity

6. Time distortions

7. Illusions, delusions and hallucinations are rare except at
high doses

8. Impaired judgment, reduced coordination and ataxia, which can
impede driving ability or lead to an increase in risk-taking
behavior

9. Emotional lability, incongruity of affect, dysphoria,
disorganized thinking, inability to converse logically, agitation,
paranoia, confusion, restlessness, anxiety, drowsiness and panic
attacks may occur, especially in inexperienced users or in those who
have taken a large dose

10. Increased appetite and short-term memory impairment are
common

These subjective responses to marijuana are pleasurable to many
humans and are associated with drug-seeking and drug-taking
(Maldonado, 2002). DHHS states that, as with most psychoactive
drugs, an individual's response to marijuana can be influenced by a
person's medical/psychiatric history as well as their experience
with drugs. Frequent marijuana users (used more than 100 times) were
better able to identify a drug effect from low-dose [Delta]\9\-THC
than infrequent users (used less than 10 times) and were less likely
to experience sedative effects from the drug (Kirk and de Wit,
1999). However, dose preferences have been demonstrated for
marijuana in which higher doses (1.95 percent [Delta]\9\-THC) are
preferred over lower doses (0.63 percent [Delta]\9\-THC) (Chait and
Burke, 1994).

DEA notes that an extensive review of the reinforcing effects of
marijuana in humans was included in DEA/DHHS's prior review of

[[Page 40570]]

marijuana (Notice of Denial of Petition, 66 FR 20038, 2001). While
additional studies have been published on the reinforcing effects of
marijuana in humans (e.g., see review by Cooper and Haney, 2009),
they are consistent with the information provided in DEA/DHHS's
prior review of this matter. Excerpts are provided below, with some
citations omitted.

Both marijuana and THC can serve as positive reinforcers in
humans. Marijuana and [Delta]\9\-THC produced profiles of behavioral
and subjective effects that were similar regardless of whether the
marijuana was smoked or taken orally, as marijuana in brownies, or
orally as THC-containing capsules, although the time course of
effects differed substantially. There is a large clinical literature
documenting the subjective, reinforcing, discriminative stimulus,
and physiological effects of marijuana and THC and relating these
effects to the abuse potential of marijuana and THC (e.g., Chait et
al., 1988; Lukas et al., 1995; Kamien et al., 1994; Chait and Burke,
1994; Chait and Pierri, 1992; Foltin et al., 1990; Azorlosa et al.,
1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992; Cone et al.,
1988; Mendelson and Mello, 1984).

These listed studies represent a fraction of the studies
performed to evaluate the abuse potential of marijuana and THC. In
general, these studies demonstrate that marijuana and THC dose-
dependently increases heart rate and ratings of "high" and "drug
liking", and alters behavioral performance measures (e.g., Azorlosa
et al., 1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992;
Kamien et al., 1994; Chait and Burke, 1994; Chait and Pierri, 1992;
Foltin et al., 1990; Cone et al., 1988; Mendelson and Mello, 1984).
Marijuana also serves as a discriminative stimulus in humans and
produces euphoria and alterations in mood. These subjective changes
were used by the subjects as the basis for the discrimination from
placebo (Chait et al., 1988).

In addition, smoked marijuana administration resulted in
multiple brief episodes of euphoria that were paralleled by rapid
transient increases in EEG alpha power (Lukas et al., 1995); these
EEG changes are thought to be related to CNS processes of
reinforcement (Mello, 1983).

To help elucidate the relationship between the rise and fall of
plasma THC and the self-reported psychotropic effects, Harder and
Rietbrock (1997) measured both the plasma levels of THC and the
psychological "high" obtained from smoking a marijuana cigarette
containing 1% THC. As can be seen from these data, a rise in plasma
THC concentrations results in a corresponding increase in the
subjectively reported feelings of being "high". However, as THC
levels drop the subjectively reported feelings of "high" remain
elevated. The subjective effects seem to lag behind plasma THC
levels. Similarly, Harder and Rietbrock compared lower doses of 0.3%
THC-containing and 0.1% THC-containing cigarettes in human subjects.

As can be clearly seen from these data, even low doses of
marijuana, containing 1%, 0.3% and even 0.1% THC, typically referred
to as "non-active", are capable of producing subjective reports
and physiological markers of being "high'.

THC and its major metabolite, 11-OH-THC, have similar
psychoactive and pharmacokinetic profiles in man (Wall et al., 1976;
DiMarzo et al., 1998; Lemberger et al., 1972). Perez-Reyes et al.
(1972) reported that THC and 11-OH-THC were equipotent in generating
a "high" in human volunteers. However, the metabolite, 11-OH-THC,
crosses the blood-brain barrier faster than the parent THC compound
(Ho et al., 1973; Perez-Reyes et al., 1976). Therefore, the changes
in THC plasma concentrations in humans may not be the best
predictive marker for the subjective and physiological effects of
marijuana in humans. Cocchetto et al. (1981) have used hysteresis
plots to clearly demonstrate that plasma THC concentration is a poor
predictor of simultaneous occurring physiological (heart rate) and
psychological ("high") pharmacological effects. Cocchetto et al.
demonstrated that the time course of tachycardia and psychological
responses lagged behind the plasma THC concentration-time profile.
As recently summarized by Martin and Hall (1997, 1998)

"There is no linear relationship between blood [THC] levels and
pharmacological effects with respect to time, a situation that
hampers the prediction of cannabis-induced impairment based on THC
blood levels (p90)".

Drug craving is an urge or desire to re-experience the drug's
effects and is considered to be one component of drug dependence, in
part responsible for continued drug use and relapse after treatment
or during periods of drug abstinence. DEA notes that Budney and
colleagues (1999) reported that 93 percent of marijuana-dependent
adults seeking treatment reported experiencing mild craving for
marijuana, and 44 percent rated their past craving as severe.
Heishman and colleagues developed in 2001 a Marijuana Craving
Questionnaire (MCQ). When they administered their MCQ to 217 current
marijuana smokers who were not attempting to quit or reduce their
marijuana use, they found that marijuana craving can be measured in
current smokers that are not seeking treatment. Most subjects (83
percent) reported craving marijuana 1-5 times per day, and 82
percent reported that each craving episode lasted 30 minutes or
less. Furthermore, they determined that craving for marijuana can be
characterized by four components: (1) compulsivity, an inability to
control marijuana use; (2) emotionality, use of marijuana in
anticipation of relief from withdrawal or negative mood; (3)
expectancy, anticipation of positive outcomes from smoking
marijuana; and (4) purposefulness, intention and planning to use
marijuana for positive outcomes.

Marijuana use has been relatively stable from 2002 to 2008, and
it continues to be the most widely used illicit drug. Evidence of
actual abuse can be defined by episodes/mentions in databases
indicative of abuse/dependence. DHHS provided in its 2006 documents
data relevant to actual abuse of marijuana including data from the
National Survey on Drug Use and Health (NSDUH; formally known as the
National Household Survey on Drug Abuse), the Drug Abuse Warning
Network (DAWN), Monitoring the Future (MTF) survey, and the
Treatment Episode Data Set (TEDS). These data collection and
reporting systems provide quantitative data on many factors related
to abuse of a particular substance, including incidence, pattern,
consequence and profile of the abuser of specific substances. DEA
provides here updates to these databases as well as additional data
on trafficking and illicit availability of marijuana using
information from databases it produces, such as the National
Forensic Laboratory Information System (NFLIS), the System to
Retrieve Information from Drug Evidence (STRIDE) and the Federal-
wide Drug Seizure System (FDSS), as well as other sources of data
specific to marijuana, including the Potency Monitoring Project and
the Domestic Cannabis Eradication and Suppression Program (DCE/SP).

1. National Survey on Drug Use and Health (NSDUH)

The National Survey on Drug Use and Health, formerly known as
the National Household Survey on Drug Abuse (NHSDA), is conducted
annually by the Department of Health and Human Service's Substance
Abuse and Mental Health Services Administration (SAMHSA). It is the
primary source of estimates of the prevalence and incidence of
pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the
United States. The survey is based on a nationally representative
sample of the civilian, non-institutionalized population 12 years of
age and older. The survey excludes homeless people who do not use
shelters, active military personnel, and residents of institutional
group quarters such as jails and hospitals.

According to the 2009 NSDUH report, marijuana was the most
commonly used illicit drug (16.7 million past month users) in the
United States. (Note that NSDUH figures on marijuana use include
hashish use; the relative proportion of hashish use to marijuana use
is very low). Marijuana was also the most widely abused drug. The
2009 NSDUH report stated that 4.3 million persons were classified
with substance dependence or abuse of marijuana in the past year
based on criteria specified in the Diagnostic and Statistical Manual
of Mental Disorders, 4th edition (DSM-IV). Among persons aged 12 or
older, the past month marijuana use in 2009 (6.6 percent) was
statistically significantly higher than in 2008 (6.1 percent). In
2008, among adults aged 18 or older who first tried marijuana at age
14 or younger, 13.5 percent were classified with illicit drug
dependence or abuse, higher than the 2.2 percent of adults who had
first used marijuana at age 18 or older.

In 2008, among past year marijuana users aged 12 or older, 15.0
percent used marijuana on 300 or more days within the previous 12
months. This translates into 3.9 million people using marijuana on a
daily or almost

[[Page 40571]]

daily basis over a 12-month period, higher than the estimate of 3.6
million (14.2 percent of past year users) in 2007. Among past month
marijuana users, 35.7 percent (5.4 million) used the drug on 20 or
more days in the past month.

2. Monitoring the Future

Monitoring the Future (MTF) is a national survey conducted by
the Institute for Social Research at the University of Michigan
under a grant from the National Institute on Drug Abuse (NIDA) that
tracks drug use trends among American adolescents in the 8th, 10th,
and 12th grades. Marijuana was the most commonly used illicit drug
reported in the 2010 MTF report. Approximately 8.0 percent of 8th
graders, 16.7 percent of the 10th graders, and 21.4 percent of 12th
graders surveyed in 2010 reported marijuana use during the past
month prior to the survey. Monitoring the Future participants
reported a statistically significant increase of daily use in the
past month in 2010, compared to 2009, 1.2 percent, 3.3 percent, and
6.1 percent of eighth, tenth and twelfth graders, respectively.

3. DAWN ED (Emergency Department)

The Drug Abuse Warning Network (DAWN) is a public health
surveillance system that monitors drug-related hospital emergency
department (ED) visits to track the impact of drug use, misuse, and
abuse in the United States. DAWN provides a picture of the impact of
drug use, misuse, and abuse on metropolitan areas and across the
nation. DAWN gathers data on drug abuse-related ED visits from a
representative sample of hospitals in the coterminous United States.
DAWN ED gathers data on emergency department visits relating to
substance use including, but not limited to, alcohol, illicit drugs,
and other substances categorized as psychotherapeutic, central
nervous system, respiratory, cardiovascular, alternative medication,
anti-infective, hormone, nutritional product and gastrointestinal
agents. For the purposes of DAWN, the term "drug abuse" applies if
the following conditions are met: (1) the case involved at least one
of the following: use of an illegal drug; use of a legal drug
contrary to directions; or inhalation of a non-pharmaceutical
substance and (2) the substance was used for one of the following
reasons: because of drug dependence; to commit suicide (or attempt
to commit suicide); for recreational purposes; or to achieve other
psychic effects.

In 2009, marijuana was involved in 376,467 ED visits, out of
1,948,312 drug-related ED visits, as estimated by DAWN ED for the
entire United States. This compares to a higher number of ED visits
involving cocaine (422,896), and lower numbers of ED visits
involving heroin (213,118) and stimulants (amphetamine,
methamphetamine) (93,562). Visits involving the other major illicit
drugs, such as MDMA, GHB, LSD and other hallucinogens, PCP, and
inhalants, were much less frequent, comparatively.

In young patients, marijuana is the illicit drug most frequently
involved in ED visits according to DAWN estimates, with 182.2 per
100,000 population aged 12 to 17, 484.8 per 100,000 population aged
18 to 20, and 360.2 per 100,000 population aged 21 to 24.

4. Treatment Episode Data Set (TEDS) System

Users can become dependent on marijuana to the point that they
seek treatment to stop abusing it or are referred to a drug abuse
treatment program. The TEDS system is part of the SAMHSA Drug and
Alcohol Services Information System. TEDS comprises data on
treatment admissions that are routinely collected by states in
monitoring their substance abuse treatment systems. The primary goal
of the TEDS is to monitor the characteristics of treatment episodes
for substances abusers. The TEDS report provides information on both
the demographic and substance use characteristics of admissions to
treatment for abuse of alcohol and drugs in facilities that report
to individual state administrative data systems. TEDS does not
include all admissions to substance abuse treatment. It includes
admissions to facilities that are licensed or certified by the state
substance abuse agency to provide substance abuse treatment (or are
administratively tracked by the agency for other reasons). In
general, facilities reporting to TEDS are those that receive state
alcohol and/or drug agency funds (including federal block grant
funds) for the provision of alcohol and/or drug treatment services.
The primary substances reported by TEDS are alcohol, cocaine,
marijuana (marijuana is considered together with hashish), heroin,
other opiates, PCP, hallucinogens, amphetamines, other stimulants,
tranquilizers, sedatives, inhalants and other/unknown. TEDS defines
Primary Substance of Abuse as the main substance of abuse reported
at the time of admission. TEDS also allows for the recording of two
other substances of abuse (secondary and tertiary). A client may be
abusing more than three substances at the time of admission, but
only three are recorded in TEDS.

Admissions for primary abuse of marijuana/hashish accounted for
16 percent of all treatment admissions reported to the TEDS system
in 2006 and 2007. In 2006, 2007 and 2008, 1,933,206, 1,920,401 and
2,016,256 people were admitted to drug and alcohol treatment in the
United States, respectively. The marijuana/hashish admissions
represented 16 percent (308,670), 16 percent (307,123) and 17.2
percent (346,679) of the total drug/alcohol treatment admissions in
2006, 2007 and 2008, respectively. In 2008, 65.8 percent of the
individuals admitted for marijuana were aged 12-17, 18-20 and 21-25
(30.5 percent, 15.3 percent and 20.0 percent, respectively). Among
the marijuana/hashish admissions in 2007 in which age of first use
was reported (286,194), 25.1 percent began using marijuana at age 12
or younger.

5. Forensic Laboratory Data

Marijuana is widely available in the United States, fueled by
increasing marijuana production at domestic grow sites as well as
increasing production in Mexico and Canada. Data on marijuana
seizures from federal, state, and local law enforcement laboratories
have indicated that there is significant trafficking of marijuana.
The National Forensic Laboratory Information System (NFLIS) is a
program sponsored by the Drug Enforcement Administration's Office of
Diversion Control. NFLIS compiles information on exhibits analyzed
in state and local law enforcement laboratories. The System to
Retrieve Information from Drug Evidence (STRIDE) is a DEA database
which compiles information on exhibits analyzed in DEA laboratories.
NFLIS and STRIDE together capture data for all substances reported
by forensic laboratory analyses. More than 1,700 unique substances
are reported to these two databases.

NFLIS showed that marijuana was the most frequently identified
drug in state and local laboratories from January 2001 through
December 2010. Marijuana accounted for between 34 percent and 38
percent of all drug exhibits analyzed during that time frame.
Similar to NFLIS, STRIDE data showed that marijuana was the most
frequently identified drug in DEA laboratories for the same
reporting period. From January 2001 through December 2010, a range
of between 17 percent and 21 percent of all exhibits analyzed in DEA
laboratories were identified as marijuana (Table 1).

Since 2001, the total number of exhibits and cases of marijuana
and the amount of marijuana seized federally has remained high and
the number of marijuana plants eradicated has considerably increased
(see data from Federal-wide Drug Seizure System and Domestic
Cannabis Eradication and Suppression Program below).

6. Federal-wide Drug Seizure System

The Federal-wide Drug Seizure System (FDSS) contains information
about drug seizures made by the Drug Enforcement Administration, the
Federal Bureau of Investigation, United States Customs and Border
Protection, and United States Immigration and Customs Enforcement,
within the jurisdiction of the United States. It also records
maritime seizures made by the United States Coast Guard. Drug
seizures made by other Federal agencies are included in the FDSS
database when drug evidence custody is transferred to one of the
agencies identified above. FDSS is now incorporated into the
National Seizure System (NSS), which is a repository for information
on clandestine laboratory, contraband (chemicals and precursors,
currency, drugs, equipment and weapons). FDSS reports total federal
drug seizures (kg) of substances such as cocaine, heroin, MDMA,
methamphetamine, and cannabis (marijuana and hashish). The yearly
volume of cannabis seized (Table 3), consistently exceeding a
thousand metric tons per year, shows that cannabis is very widely
trafficked in the United States.

Table 3--Total Federal Seizures of Cannabis
[Expressed in kg]

2002

2003

2004

2005

2006

2007

2008

2009

2009

Cannabis

1,103,173

1,232,711

1,179,230

1,116,977

1,141,915

1,459,220

1,590,793

1,911,758

1,858,808

Marijuana

1,102,556

1,232,556

1,179,064

1,116,589

1,141,737

1,458,883

1,590,505

1,910,775

1,858,422

Hashish

618

155

166

388

178

338

289

983

386

7. Potency Monitoring Project

Rising availability of high potency (i.e., with high [Delta]\9\-
THC concentrations) marijuana has pushed the average marijuana
potency to its highest recorded level. The University of
Mississippi's Potency Monitoring Project (PMP), through a contract
with the National Institute on Drug Abuse (NIDA), analyzes and
compiles data on the [Delta]\9\-THC concentrations of cannabis,
hashish and hash oil samples provided by DEA regional laboratories
and by state and local police agencies.

DEA notes studies showing that when given the choice between
low- and high-potency marijuana, subjects chose the high-potency
marijuana significantly more often than the low-potency marijuana
(Chait and Burke, 1994), supporting the hypothesis that the
reinforcing effects of marijuana, and possibly its abuse liability,
are positively related to THC content.

[[Page 40573]]

8. The Domestic Cannabis Eradication and Suppression Program

The Domestic Cannabis Eradication and Suppression Program (DCE/
SP) was established in 1979 to reduce the supply of domestically
cultivated marijuana in the United States. The program was designed
to serve as a partnership between federal, state, and local
agencies. Only California and Hawaii were active participants in the
program at its inception. However, by 1982 the program had expanded
to 25 states and by 1985 all fifty states were participants.
Cannabis is cultivated in remote locations and frequently on public
lands. Data provided by the DCE/SP (Table 4) shows that in 2009,
there were 9,980,038 plants eradicated in outdoor cannabis
cultivation areas in the United States. Marijuana is illicitly grown
in all states. Major domestic outdoor cannabis cultivation areas
were found in California, Kentucky, Tennessee and Hawaii.
Significant quantities of marijuana were also eradicated from indoor
cultivation operations. There were 414,604 indoor plants eradicated
in 2009 compared to 217,105 eradicated in 2000. As indoor
cultivation is generally associated with plants that have higher
concentrations of [Delta]\9\-THC, the larger numbers of indoor grow
facilities may be impacting the higher average [Delta]\9\-THC
concentrations of seized materials.

The recent statistics from these various surveys and databases
show that marijuana continues to be the most commonly used illicit
drug, with considerable rates of heavy abuse and dependence. They
also show that marijuana is the most readily available illicit drug
in the United States.

The petitioner states that, "The abuse potential of cannabis is
insufficient to justify the prohibition of medical use." The
petitioner also states that, "[s]everal studies demonstrate that
abuse rates for cannabis are lower than rates for other common
drugs." (Exh. C, Section IV(16), pg. 92).

DHHS states, to the contrary, "the large number of individuals
using marijuana on a regular basis, its widespread use, and the vast
amount of marijuana that is available for illicit use are indicative
of the high abuse potential for marijuana." Indeed, the data
presented in this section shows that marijuana has a high potential
for abuse as determined using the indicators identified in the CSA's
legislative history. Both clinical and preclinical studies have
demonstrated that marijuana and its principal psychoactive
constituent [Delta]\9\-THC possess the attributes associated with
drugs of abuse. They function as positive reinforcers and as
discriminative stimuli to maintain drug-seeking behavior.

In addition, marijuana is the most highly abused and trafficked
illicit substance in the United States. Chronic abuse has resulted
in a considerable number of individuals seeking substance abuse
treatment according to national databases such as TEDS. Abuse of
marijuana is associated with significant public health and safety
risks that are described under factors 2, 6 and 7.

The issue of whether marijuana has a currently accepted medical
use is discussed under Factor 3.

[[Page 40574]]

The petitioner claims that, "[[hellip]]widespread use of
marijuana without dependency supports the argument that marijuana is
safe for use under medical supervision." (Exh. C, Section IV(15),
pg. 87).

Petitioner's claim of widespread use without dependency is not
supported by abuse-related data. In particular, this claim
disregards the high numbers of admissions to treatment facilities
for marijuana abuse. Indeed, TEDS admissions for primary abuse of
marijuana/hashish accounted for roughly 17 percent of all treatment
admissions in 2008. In 2008, 2,016,256 people were admitted to drug
and alcohol treatment in the United States and 346,679 of those
admissions were for marijuana/hashish abuse. These drug treatment
numbers are not consistent with this claim. Marijuana is not safe
for use under medical supervision, and this point is addressed
further in Factor 3.

The petitioner also claims that, "Data on both drug treatment
and emergency room admissions also distinguishes the abuse potential
of marijuana from that of other drugs and establishes its relative
abuse potential as lower than schedule I drugs such as heroin and
schedule II drugs such as cocaine." (Exh. C, Section IV(17), pg.
99). The petitioner then presents data from TEDS in 1998, in which a
larger proportion of all marijuana treatment admissions are referred
to by the criminal justice system (54 percent), compared to much
smaller percentages for heroin and cocaine. The petitioner argues
that the abuse potential of these other drugs is more severe such
that addicts seek treatment on their own or through persuasion of
their associates, and claims that this difference establishes
marijuana's relative abuse potential as lower than the other drugs.

Petitioner's claim is not supported by an examination of the
absolute numbers of admissions for treatment for each drug
discussed. Regardless of proportions of referrals from the criminal
justice systems, the absolute numbers of admissions for treatment
for marijuana, heroin, or cocaine dependence are very high.
Furthermore, data from TEDS in 2007 (SAMHSA, 2009) show that both
primary marijuana and methamphetamine/amphetamine admissions had the
largest proportion of admissions referred through the criminal
justice system (57 percent each), followed by PCP (54 percent). Both
methamphetamine/amphetamine and PCP have very high potential for
abuse (Lile, 2006; Crider, 1986). Accordingly, this illustrates that
it is not possible to establish or predict relative abuse potentials
from the ranking of proportions of treatment admissions referred by
the criminal justice system.

FACTOR 2: SCIENTIFIC EVIDENCE OF THE DRUG'S PHARMACOLOGICAL EFFECTS, IF
KNOWN

DHHS states that there are abundant scientific data available on
the neurochemistry, toxicology, and pharmacology of marijuana.
Following is a summary of the current scientific understanding of
the endogenous cannabinoid system and of marijuana's pharmacological
effects, including its effects on the cardiovascular, respiratory,
and immune systems, as well as its effects on mental health and
cognitive function and the effect of prenatal exposure to marijuana.

Neurochemistry of the Psychoactive Constituents of Marijuana

DHHS states that of 483 natural constituents identified in
marijuana, 66 are classified as cannabinoids (Ross and El Sohly,
1995). Cannabinoids are not known to exist in plants other than
marijuana and most of the cannabinoid compounds have been identified
chemically. The activity of marijuana is largely attributed to
[Delta]\9\-THC (Wachtel et al., 2002).

DEA notes that [Delta]\9\-THC and delta-8-tetrahydrocannabinol
([Delta]\8\-THC) are the only known compounds in the cannabis plant
which show all the psychoactive effects of marijuana. [Delta]\9\-THC
is more abundant than [Delta]\8\-THC and [Delta]\9\-THC
concentrations vary within portions of the cannabis plant (Hanus and
Subiv[aacute], 1989; Hanus et al., 1975). The pharmacological
activity of [Delta]\9\-THC is stereospecific: the (-)-trans isomer
is 6-100 times more potent than the (+)-trans isomer (Dewey et al.,
1984).

The mechanism of action of [Delta]\9\-THC was verified with the
cloning of cannabinoid receptors, first from rat brain tissue
(Matsuda et al., 1990) and then from human brain tissue (Gerard et
al., 1991). Two cannabinoid receptors have been identified and
characterized, CB1 and CB2 (Piomelli, 2005).
Autoradiographic studies have provided information on the
distribution of CB1 and CB2 receptors. High
densities of CB1 receptors are found in the basal
ganglia, hippocampus, and cerebellum of the brain (Howlett et al.,
2004; Herkenham et al., 1990; Herkenham, 1992). These brain regions
are associated with movement coordination and cognition and the
location of CB1 receptors in these areas may explain
cannabinoid interference with these functions. Although
CB1 receptors are predominantly expressed in the brain,
they have also been detected in the immune system (Bouaboula et al.,
1993). CB2 receptors are primarily located in B
lymphocytes and natural killer cells of the immune system and it is
believed that this receptor is responsible for mediating
immunological effects of cannabinoids (Galiegue et al., 1995).
Recently, however, CB2 receptors have been localized in
the brain, primarily in the cerebellum and hippocampus (Gong et al.,
2006).

Cannabinoid receptors are linked to an inhibitory G-protein
(Breivogel and Childers, 2000). When the receptor is activated,
adenylate cyclase activity is inhibited, preventing the conversion
of adenosine triphosphate (ATP) to the second messenger cyclic
adenosine monophosphate (cAMP). Other examples of inhibitory-coupled
receptors include opioid, muscarinic cholinergic, alpha2-
adrenoreceptors, dopamine and serotonin receptors. However, several
studies also suggest a link to stimulatory G-proteins, through which
activation of CB1 stimulates adenylate cyclase activity
(Glass and Felder, 1997; Maneuf and Brotchie, 1997; Felder et al.,
1998).

Activation of CB1 receptors inhibits N-and P/Q-type
calcium channels and activate inwardly rectifying potassium channels
(Mackie et al., 1995; Twitchell et al., 1997). Inhibition of N-type
calcium channels decreases neurotransmitter release from a number of
tissues and may be the mechanism by which cannabinoids inhibit
acetylcholine, norepinephrine, and glutamate release from specific
areas of the brain. These effects on G protein-mediated pathways and
on calcium and potassium channels may represent potential cellular
mechanisms underlying the antinociceptive and psychoactive effects
of cannabinoids (Ameri, 1999).

Delta\9\-THC displays similar affinity for both cannabinoid
receptors but behaves as a weak agonist at CB2 receptors,
based on inhibition of adenylate cyclase. The identification of
synthetic cannabinoid ligands that selectively bind to
CB2 receptors but do not have the typical [Delta]\9\-THC-
like psychoactive properties, along with the respective anatomical
distribution of the two receptor subtypes suggests that the
psychoactive effects of cannabinoids are mediated through the
activation of CB1 receptors (Hanus et al., 1999).
Naturally occurring cannabinoids and synthetic cannabinoid agonists
(such as WIN-55,212-2 and CP-55,940) produce hypothermia, analgesia,
hypoactivity, and catalepsy in addition to their psychoactive
effects.

In 2000, two endogenous cannabinoid receptor agonists were
discovered, anandamide and arachidonyl glycerol (2-AG). Anandamide
is a low efficacy agonist (Breivogel and Childers, 2000) and 2-AG is
a highly efficacious agonist (Gonsiorek et al., 2000). These
endogenous ligands are present in both central and peripheral
tissues. The physiological role of these endogenous ligands is an
active area of research (Martin et al., 1999).

In summary, two receptors have been cloned, CB1
(found in the central nervous system) and CB2 (predominantly found
in the periphery), that bind [Delta]\9\-THC and other cannabinoids.
Activation of these inhibitory G-protein-coupled receptors inhibits
calcium channels and adenylate cyclase. Endogenous cannabinoid
agonists have been identified, anandamide and arachidonyl glycerol
(2-AG).

Pharmacological Effects of Marijuana

Marijuana produces a number of central nervous system effects.
Many of these effects are directly related to the abuse potential of
marijuana, and are discussed in Factor 1. Other effects are
discussed herein.

Cardiovascular and Autonomic Effects

DHHS states that acute use of marijuana causes an increase in
heart rate (tachycardia) and may cause a modest increase in blood
pressure as well (Capriotti et al., 1988; Benowitz and Jones, 1975).
Conversely, chronic exposure to marijuana will produce a decrease in
heart rate (bradycardia) and decrease of blood pressure. In heavy
smokers of marijuana, the degree of increased heart rate is
diminished due to the development of tolerance (Jones, 2002 and
Sidney, 2002). These effects are thought to be mediated through
peripherally located, presynaptic CB1 receptor inhibition
of norepinephrine release with possible direct activation of
vascular cannabinoid receptors (Wagner et al., 1998).

[[Page 40575]]

DHHS cites a review (Jones, 2002) of studies showing that smoked
marijuana causes orthostatic hypotension (sympathetic insufficiency,
a sudden drop in blood pressure upon standing up) often accompanied
by dizziness. DHHS states that tolerance can develop to this effect.

DEA further notes studies in which marijuana has been
administered under controlled conditions to marijuana-experienced
users that showed that marijuana causes a substantial increase,
compared to placebo, in heart rate (tachycardia) ranging from 20
percent to 100 percent above baseline. This effect was seen as
usually greatest starting during the 10 minutes or so it takes to
smoke a marijuana cigarette and lasting 2 to 3 hours (reviewed in
Jones et al., 2002).

DEA also notes a randomized, double-blind, placebo-controlled
study by Mathew and colleagues (2003) that examined pulse rate,
blood pressure (BP), and plasma [Delta]\9\-THC levels during
reclining and standing for 10 minutes before and after smoking one
marijuana cigarette (3.55 percent [Delta]\9\-THC) by twenty-nine
volunteers. Marijuana induced postural dizziness, with 28 percent of
subjects reporting severe symptoms. Intoxication and dizziness
peaked immediately after drug intake. The severe dizziness group
showed the most marked postural drop in blood pressure and showed a
drop in pulse rate after an initial increase during standing.

Respiratory Effects

Both acute and chronic respiratory effects are associated with
marijuana smoking.

DHHS states that acute exposure to marijuana produces transient
bronchodilation (Gong et al., 1984). DHHS states that long-term use
of smoked marijuana can lead to increased frequency of chronic
cough, increased sputum, large airway obstruction, as well as
cellular inflammatory histopathological abnormalities in bronchial
epithelium (Adams and Martin, 1996; Hollister, 1986).

DHHS states that the evidence that marijuana may lead to cancer
is inconsistent, with some studies suggesting a positive correlation
while others do not. DHHS cited a large clinical study with 1,650
subjects in which no positive correlation was found between
marijuana use and lung cancer (Tashkin et al., 2006). This finding
held true regardless of the extent of marijuana use when both
tobacco use and other potential confounding factors were controlled.
DHHS also cites other studies reporting lung cancer occurrences in
young marijuana users with no history of tobacco smoking (Fung et
al., 1999), and suggesting a dose-dependent effect of marijuana on
the risk of head and neck cancer (Zhang et al., 1999).

DEA notes the publication of a more recent case-control study of
lung cancer in adults under 55 years of age, conducted in New
Zealand by Aldington and colleagues (2008). Interviewer-administered
questionnaires were used to assess possible risk factors, including
cannabis use. In total, 79 cases of lung cancer and 324 controls
were included in the study. The risk of lung cancer increased 8
percent (95 percent confidence interval (CI) 2-15) for each joint-
year of cannabis smoking (one joint-year being equivalent to one
joint per day for a year), after adjustment for confounding
variables including cigarette smoking; it went up 7 percent (95
percent CI 5-9) for each pack-year of cigarette smoking (one pack-
year being equivalent to one pack per day for a year), after
adjustment for confounding variables including cannabis smoking.
Thus, a major differential risk between cannabis and cigarette
smoking was observed, with one joint of cannabis being similar to 20
cigarettes for risk of lung cancer. Users reporting over 10.5 joint-
years of exposure had a significantly increased risk of developing
lung cancer (relative risk 5.7 (95 percent CI 1.5-21.6)) after
adjustment for confounding variables including cigarette smoking.
DEA notes that the authors of this study concluded from their
results that long-term cannabis use increases the risk of lung
cancer in young adults.

Some studies discuss marijuana smoke and tobacco smoke. DHHS
states that chronic exposure to marijuana smoke is considered to be
comparable to tobacco smoke with respect to increased risk of cancer
and lung damage. DEA notes studies showing that marijuana smoke
contains several of the same carcinogens and co-carcinogens as
tobacco smoke and suggesting that pre-cancerous lesions in bronchial
epithelium also seem to be caused by long-term marijuana smoking
(Roth et al., 1998).

In summary, studies are still needed to clarify the impact of
marijuana on the risk of developing lung cancer as well as head and
neck cancer. DHHS states that the evidence that marijuana may lead
to cancer is inconsistent, with some studies suggesting a positive
correlation while others do not.

Endocrine Effects

DHHS states that [Delta]\9\-THC reduces binding of the
corticosteroid dexamethasone in hippocampal tissue from
adrenalectomized rats and acute [Delta]\9\-THC releases
corticosterone, with tolerance developing to this effect with
chronic administration (Eldridge et al., 1991). These data suggest
that [Delta]\9\-THC may interact with the glucocorticoid receptor
system.

DHHS cites a study (Sarfaraz et al., 2005) which showed that the
cannabinoid agonist WIN 55,212-2 induces apoptosis in prostate
cancer cells growth and decreases expression of androgen receptors.
DHHS states that this data suggests a potential therapeutic value
for cannabinoid agonists in the treatment of prostate cancer, an
androgen-stimulated type of carcinoma.

In summary, while animal studies have suggested that
cannabinoids can alter multiple hormonal systems, the effects in
humans, in particular the consequences of long-term marijuana abuse,
remain unclear.

Immune System Effects

DHHS states that cannabinoids alter immune function but that
there can be differences between the effects of synthetic, natural,
and endogenous cannabinoids (Croxford and Yamamura, 2005).

DHHS cites a study by Roth et al. (2005) that examined the
effect of [Delta]\9\-THC exposure on immune function and response to
HIV infection in immunodeficient mice that were implanted with human
blood cells infected with HIV. The study shows that exposure to
[Delta]\9\-THC in vivo suppresses immune function, increases HIV co-
receptor expression and acts as a cofactor to enhance HIV
replication. DEA notes that the authors of this study state that
their results suggest a dynamic interaction between [Delta]\9\-THC,
immunity, and the pathogenesis of HIV and support epidemiologic
studies that have identified marijuana use as a risk factor for HIV
infection and the progression of AIDS. However, DHHS discusses a
recent study by Abrams et al. (2003) that investigated the effect of
marijuana on immunological functioning in 67 AIDS patients who were
taking protease inhibitors. Subjects received one of three
treatments, three times a day: smoked marijuana cigarette containing
3.95 percent [Delta]\9\-THC; oral tablet containing [Delta]\9\-THC
(2.5 mg oral dronabinol); or oral placebo. There were no changes in
HIV-RNA levels between groups, demonstrating no short-term adverse
virologic effects from using cannabinoids.

DEA notes a review suggesting that [Delta]\9\-THC and
cannabinoids decrease resistance to microbial infections in
experimental animal models and in vitro (see review by Cabral and
Staab, 2005). Various studies have been conducted in drug-abusing
human subjects, experimental animals exposed to marijuana smoke or
injected with cannabinoids, and in in vitro models using immune cell
cultures treated with various cannabinoids. DEA notes that for the
most part, these studies suggest that cannabinoids modulate the
function of various cells of the human immune system, including T-
and B-

In addition to studies examining cannabinoid effects on immune
cell function, DEA also notes other reports which have documented
that cannabinoids modulate resistance to various infectious agents.
Viruses such as herpes simplex virus and murine retrovirus have been
studied as well as bacterial agents such as members of the genera
Staphylococcus, Listeria, Treponema, and Legionella. These studies
suggest that cannabinoids modulate host resistance, especially the
secondary immune response (reviewed in Cabral and Dove-Pettit,
1998).

Finally, DEA notes a review suggesting that cannabinoids
modulate the production and function of cytokines as well as
modulate the activity of network cells such as macrophages and T
helper cells. Cytokines are the chemicals produced by cells of the
immune system in order to communicate and orchestrate the attack.
Binding to specific receptors on target cells, cytokines recruit
many other cells and substances to the field of action. Cytokines
also encourage cell growth, promote cell activation, direct cellular
traffic, and destroy target cells (see review by Klein et al.,
2000).

In summary, as DHHS states, cannabinoids alter immune function,
but there can be differences between the effects of synthetic,
natural, and endogenous cannabinoids. While there is a large body of
evidence to suggest that [Delta]\9\-THC alters immune function,
research is still needed to clarify the effects of cannabinoids and
marijuana on the immune system in humans, in particular the risks
posed by smoked marijuana in immunocompromized individuals.

Association with Psychosis

The term psychosis is generally used in research as a generic
description of severe mental illnesses characterized by the presence
of delusions, hallucinations and other associated cognitive and
behavioral impairments. Psychosis is measured either by using
standardized diagnostic criteria for psychotic conditions such as
schizophrenia or by using validated scales that rank the level of
psychotic symptoms from none to severe (Fergusson et al., 2006).

DHHS states that extensive research has been conducted recently
to investigate whether exposure to marijuana is associated with
schizophrenia or other psychoses. DHHS states that, at the time of
their review, the data does not suggest a causative link between
marijuana use and the development of psychosis.

DHHS discusses an early epidemiological study conducted by
Andreasson and colleagues (1987), which examined the link between
psychosis and marijuana use. In this study, 45,000 18- and 19-year-
old male Swedish subjects provided detailed information on their
drug-taking history. The incidence of schizophrenia was then
recorded over the next 15 years. Those individuals who claimed, on
admission, to have taken marijuana on more than 50 occasions were
six times more likely to be diagnosed with schizophrenia in the
following 15 years than those who had never consumed the drug. When
confounding factors were taken into account, the risk of developing
schizophrenia remained statistically significant. The authors
concluded that marijuana users who are vulnerable to developing
psychoses are at the greatest risk for schizophrenia. DHHS states
that therefore marijuana per se does not appear to induce
schizophrenia in the majority of individuals who try or continue to
use the drug.

DHHS discusses another large longitudinal study in which the
prevalence of schizophrenia was modeled against marijuana use across
birth cohorts in Australia from 1940 to 1979 (Degenhardt et al.,
2003). The authors found that marijuana use may precipitate
disorders in vulnerable individuals and worsen the course of the
disorder among those that have already developed it. They did not
find any causal relationship between marijuana use and increased
incidence of schizophrenia.

DEA notes that Degenhardt and colleagues (2003) acknowledged
that several environmental risk factors for schizophrenia had been
reduced (i.e., poor maternal nutrition, infectious disease and poor
antenatal and prenatal care) and that the diagnostic criteria for
schizophrenia had changed over the span of this study making the
classification of schizophrenia more rigorous. These confounders
could reduce the reported prevalence of schizophrenia.
DHHS also discusses several longitudinal studies that found a
dose-response relationship between marijuana use and an increasing
risk of psychosis among those who are vulnerable to developing
psychosis (Fergusson et al., 2005; van Os et al., 2002).

DEA notes several longitudinal studies (Arseneault et al., 2002,
Caspi et al., 2005; Henquet et al., 2005) that found increased rates
of psychosis or psychotic symptoms in people using cannabis.
Finally, DEA notes some studies that observe that individuals with
psychotic disorders have higher rates of cannabis use compared to
the general population (Regier et al., 1990; Green et al., 2005).

DEA also notes that, more recently, Moore and colleagues (2007)
performed a meta-analysis of the longitudinal studies on the link
between cannabis use and subsequent psychotic symptoms. Authors
observed that there was an increased risk of any psychotic outcome
in individuals who had ever used cannabis (pooled adjusted odds
ratio=1.41, 95 percent CI 1.20-1.65). Furthermore, findings were
consistent with a dose-response effect, with greater risk in people
who used cannabis most frequently (2.09, 1.54-2.84). The authors
concluded that their results support the view that cannabis
increases risk of psychotic outcomes independently of confounding
and transient intoxication effects.

DEA also notes another more recent study examining the
association between marijuana use and psychosis-related outcome in
pairs of young adult siblings in Brisbane, Australia (McGrath et
al., 2010). This study found a dose-response relationship where the
longer the duration of time since the first cannabis use, the higher
the risk of psychosis-related outcome. Those patients with early-
onset psychotic symptoms were also likely to report early marijuana
use. Authors suggest that their results support the hypothesis that
early cannabis use is a risk-modifying factor for psychosis-related
outcomes in young adults.

Cognitive Effects

DHHS states that acute administration of smoked marijuana
impairs performance on tests of learning, associative processes, and
psychomotor behavior (Block et al., 1992; Heishman et al., 1990).
Marijuana may therefore considerably interfere with an individual's
ability to learn in a classroom or to operate motor vehicles. DHHS
cites a study conducted by Kurzthalar and colleagues (1999) with
human volunteers, in which the administration of 290 [mu]g/kg of
[Delta]\9\-THC in a smoked cigarette resulted in impaired perceptual
motor speed and accuracy, skills of paramount importance for safe
driving. Similarly, administration of 3.95 percent [Delta]\9\-THC in
a smoked cigarette increased disequilibrium measures, as well as the
latency in a task of simulated vehicle braking (Liguori et al.,
1998).

DHHS states that the effects of marijuana may not be fully
resolved until at least one day after the acute psychoactive effects
have subsided, following repeated administration. Heishman and
colleagues (1988) showed that impairment on memory tasks persists
for 24 hours after smoking marijuana cigarettes containing 2.57
percent [Delta]\9\-THC. However, Fant and colleagues (1998) showed
minimal residual alterations in subjective or performance measures
the day after subjects were exposed to 1.8 percent or 3.6 percent
smoked [Delta]\9\-THC.

DHHS discussed a study by Lyons and colleagues (2004) on the
neuropsychological consequences of regular marijuana use in fifty-
four monozygotic male twin pairs, with one subject being a regular
user and its co-twin a non-user, and neither twin having used any
other illicit drug regularly. Marijuana-using twins significantly
differed from their non-using co-twins on the general intelligence
domain. However, only one significant difference was noted between
marijuana-using twins and their non-using co-twins on measures of
cognitive functioning. Authors of the study proposed that the
results indicate an absence of any marked long-term residual effects
of marijuana use on cognitive abilities. This conclusion is similar
to the results found by Lyketsos and colleagues (1999), who
investigated the possible adverse effects of cannabis use on
cognitive decline after 12 years in persons under 65 years of age.
There were no significant differences in cognitive decline between
heavy users, light users, and nonusers of cannabis. The authors
conclude that over long time periods, in persons under age 65 years,
cognitive decline occurs in all age groups. This decline is closely
associated with aging and educational level but does not appear to
be associated with cannabis use.

DEA notes that while Lyketsos and colleagues (1999) propose that
their results

[[Page 40577]]

provide strong evidence of the absence of a long term residual
effect of cannabis use on cognition, they also acknowledge a number
of limitations to their study. Notably, authors remark that it is
possible that some cannabis users in the study may have used
cannabis on the day the test was administered. Given the acute
effects on cannabis on cognition, this would have tended to reduce
their test score on that day. This may have adversely affected
accurate measurement of test score changes over time in cannabis
users. The authors also noted, as another important limitation, that
the test used is not intended for the purpose for which it was used
in this study and is not a very sensitive measure of cognitive
decline, even though it specifically tests memory and attention.
Thus, small or subtle effects of cannabis use on cognition or
psychomotor speed may have been missed.

DHHS also discussed a study by Solowij and colleagues (2002)
which examined the effects of duration of cannabis use on specific
areas of cognitive functioning among users seeking treatment for
cannabis dependence. They compared 102 near-daily cannabis users (51
long-term users: mean, 23.9 years of use; 51 shorter-term users:
mean, 10.2 years of use) with 33 nonuser controls. They collected
measures from nine standard neuropsychological tests that assessed
attention, memory, and executive functioning, and that were
administered prior to entry to a treatment program and following a
median 17-hour abstinence. Authors found that long-term cannabis
users performed significantly less well than shorter-term users and
controls on tests of memory and attention. Long-term users showed
impaired learning, retention, and retrieval compared with controls.
Both user groups performed poorly on a time estimation task.
Performance measures often correlated significantly with the
duration of cannabis use, being worse with increasing years of use,
but were unrelated to withdrawal symptoms and persisted after
controlling for recent cannabis use and other drug use. Authors of
this study state that their results support the hypothesis that
long-term heavy cannabis users show impairments in memory and
attention that endure beyond the period of intoxication and worsen
with increasing years of regular cannabis use.

DHHS discussed a study by Pope and colleagues (2003) which
reported no differences in neuropsychological performance in early-
or late-onset users compared to non-using controls, after adjustment
for intelligence quotient (IQ). In another cohort of chronic, heavy
marijuana users, some deficits were observed on memory tests up to a
week following supervised abstinence but these effects disappeared
by day 28 of abstinence (Pope et al., 2002). The authors concluded
that "cannabis-associated cognitive deficits are reversible and
related to recent cannabis exposure rather than irreversible and
related to cumulative lifetime use." Conversely, DHHS notes that
other investigators have reported persistent neuropsychological
deficits in memory, executive functioning, psychomotor speed, and
manual dexterity in heavy marijuana smokers who had been abstinent
for 28 days (Bolla et al., 2002). Furthermore, when dividing the
group into light, middle, and heavy user groups, Bolla and
colleagues (2002) found that the heavy user group performed
significantly below the light user group on 5 of 35 measures. A
follow-up study of heavy marijuana users noted decision-making
deficits after 25 days of abstinence (Bolla et al., 2005). When IQ
was contrasted in adolescents 9-12 years of age and at 17-20 years
of age, current heavy marijuana users showed a 4-point reduction in
IQ in later adolescence compared to those who did not use marijuana
(Fried et al., 2002).

DHHS states that age of first use may be a critical factor in
persistent impairment from chronic marijuana use. Individuals with a
history of marijuana-only use that began before the age of 16 were
found to perform more poorly on a visual scanning task measuring
attention than individuals who started using marijuana after 16
(Ehrenreich et al., 1999). DHHS's document noted that Kandel and
Chen (2000) assert that the majority of early-onset marijuana users
do not go on to become heavy users of marijuana, and those that do
tend to associate with delinquent social groups.

DEA notes an additional recent study that indicates that because
neuromaturation continues through adolescence, results on the long-
lasting cognitive effects of marijuana use in adults cannot
necessarily generalize to adolescent marijuana users. Medina and
colleagues (2007) examined neuropsychological functioning in 31
adolescent abstinent marijuana users, after a period of abstinence
from marijuana of 23 to 28 days, and in 34 demographically similar
control adolescents, all 16-18 years of age. After controlling for
lifetime alcohol use and depressive symptoms, adolescent marijuana
users demonstrated slower psychomotor speed (p .05), and poorer
complex attention (p .04), story memory (p .04), and planning and
sequencing ability (p .001) compared with nonusers. The number of
lifetime marijuana use episodes was associated with poorer cognitive
function, even after controlling for lifetime alcohol use. The
general pattern of results suggested that, even after a month of
monitored abstinence, adolescent marijuana users demonstrate subtle
neuropsychological deficits compared with nonusers. The authors of
this study suggest that frequent marijuana use during adolescence
may negatively influence neuromaturation and cognitive development.

In summary, acute administration of marijuana impairs
performance on tests of learning, associative processes, and
psychomotor behavior. The effects of chronic marijuana use have also
been studied. While a few studies did not observe strong persistent
neurocognitive consequences of long-term cannabis use (Lyketsos et
al., 1999; Lyons et al., 2004), others provide support for the
existence of persistent consequences (Bolla et al., 2002, 2005). The
cognitive impairments that are observed 12 hours to seven days after
marijuana use (Messinis et al., 2006; Solowij et al., 2002; Harrison
et al., 2002), and that persist beyond behaviorally detectable
intoxication, are noteworthy and may have significant consequences
on workplace performance and safety, academic achievement, and
automotive safety. In addition, adolescents may be particularly
vulnerable to the long-lasting deleterious effects of marijuana on
cognition. The overall significant effect on general intelligence as
measured by IQ should also not be overlooked.

Behavioral Effects of Prenatal Exposure

The impact of in utero marijuana exposure on performance in a
series of cognitive tasks has been studied in children of various
ages. DHHS concludes in its analysis of the presently examined
petition that since many marijuana users have abused other drugs, it
is difficult to determine the specific impact of marijuana on
prenatal exposure. Fried and Watkinson (1990) found that four year
old children of heavy marijuana users have deficits in memory and
verbal measures. Maternal marijuana use is predictive of poorer
performance on abstract/visual reasoning tasks of three year old
children (Griffith et al., 1994) and an increase in omission errors
on a vigilance task of six year olds (Fried et al., 1992). When the
effect of prenatal exposure in nine to 12 year old children is
analyzed, in utero exposure to marijuana is negatively associated
with executive function tasks that require impulse control, visual
analysis, and hypothesis testing (Fried et al., 1998).

DEA notes studies showing that [Delta]\9\-THC passes the
placental barrier (Idanpaan-Heikkila et al., 1969) and that fetal
blood concentrations are at least equal to those found in the
mother's blood (Grotenhermen, 2003).

In summary, smoked marijuana exerts a number of cardiovascular
and respiratory effects, both acutely and chronically. Marijuana's
main psychoactive ingredient [Delta]\9\-THC alters immune function.
The cognitive impairments caused by marijuana use that persist
beyond behaviorally detectable intoxication may have significant
consequences on workplace performance and safety, academic
achievement, and automotive safety, and adolescents may be
particularly vulnerable to marijuana's cognitive effects. Prenatal
exposure to marijuana was linked to children's poorer performance in
a number of cognitive tests.

FACTOR 3: THE STATE OF THE CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE
DRUG OR SUBSTANCE

DHHS states that marijuana is a mixture of the dried leaves and
flowering tops of the cannabis plant (Agurell et al., 1984; Graham,

[[Page 40578]]

1976; Mechoulam, 1973). These portions of the plant have the highest
levels of [Delta]\9\-THC, the primary psychoactive ingredient in
marijuana. The most potent product (i.e., that having the highest
percentage of [Delta]\9\-THC) of dried material is sinsemilla,
derived from the unpollinated flowering tops of the female cannabis
plant. Generally, this potent marijuana product is associated with
indoor grow sites and may have a [Delta]\9\-THC content of 15 to 20
percent or more. Other, less common forms of marijuana found on the
illicit market are hashish and hashish oil. Hashish is a [Delta]\9\-
THC-rich resinous material of the cannabis plant which is dried and
compressed into a variety of forms (balls, cakes or sticks). Dried
pieces are generally broken off and smoked. [Delta]\9\-THC content
is usually about five percent. The Middle East, North Africa and
Pakistan/Afghanistan are the main sources of hashish. Hashish oil is
produced by extracting the cannabinoids from plant material with a
solvent. Hashish oil is a light to dark brown viscous liquid with a
[Delta]\9\-THC content of about 15 percent. The oil is often
sprinkled on cigarettes, allowed to dry, and then smoked.

Chemistry

DHHS states that some 483 natural constituents have been
identified in marijuana, including 66 compounds that are classified
as cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not
known to exist in plants other than marijuana, and most naturally
occurring cannabinoids have been identified chemically. The
psychoactive properties of cannabis are attributed to one or two of
the major cannabinoid substances, namely delta-9-
tetrahydrocannabinol ([Delta]\9\-THC) and delta-8-
tetrahydrocannabinol ([Delta]\8\-THC). Other natural cannabinoids,
such as cannabidiol (CBD) and cannabinol (CBN), have been
characterized. CBD does not possess [Delta]\9\-THC-like
psychoactivity. Its pharmacological properties appear to include
anticonvulsant, anxiolytic and sedative properties (Agurell et al.,
1984, 1986; Hollister, 1986).

DHHS states that [Delta]\9\-THC is an optically active resinous
substance, extremely lipid soluble, and insoluble in water.
Chemically, [Delta]\9\-THC is known as (6aR-trans)-6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-1-ol or (-
)[Delta]\9\-(trans)-tetrahydrocannabinol. The pharmacological
activity of [Delta]\9\-THC is stereospecific: the (-)-trans isomer
is 6-100 times more potent than the (+)-trans isomer (Dewey et al.,
1984).

DEA notes a review of the contaminants and adulterants that can
be found in marijuana (McPartland, 2002). In particular, DEA notes
that many studies have reported contamination of both illicit and
NIDA-grown marijuana with microbial contaminants, bacterial or
fungal (McLaren et al., 2008; McPartland, 1994, 2002; Ungerleider et
al., 1982; Taylor et al., 1982; Kurup et al., 1983). Other microbial
contaminants include Klebsiella pneumoniae, salmonella enteritidis,
and group D Streptococcus (Ungerlerder et al., 1982; Kagen et al.,
1983; Taylor et al., 1982). DEA notes that a review by McLaren and
colleagues (2008) discusses studies showing that heavy metals
present in soil may also contaminate cannabis, and states that these
contaminants have the potential to harm the user without harming the
plant. Other sources of contaminants discussed by McLaren and
colleagues (2008) include growth enhancers and pest control products
related to marijuana cultivation and storage.

Human Pharmacokinetics

DHHS states that marijuana is generally smoked as a cigarette
(weighing between 0.5 and 1.0 gm; Jones, 1980) or in a pipe. It can
also be taken orally in foods or as extracts of plant material in
ethanol or other solvents. The absorption, metabolism, and
pharmacokinetic profile of [Delta]\9\-THC (and other cannabinoids)
in marijuana or other drug products containing [Delta]\9\-THC vary
with route of administration and formulation (Adams and Martin,
1996; Agurell et al., 1984, 1986). When marijuana is administered by
smoking, [Delta]\9\-THC in the form of an aerosol is absorbed within
seconds. The psychoactive effects of marijuana occur immediately
following absorption, with mental and behavioral effects measurable
up for to six hours after absorption (Grotenhermen, 2003; Hollister,
1986, 1988). [Delta]\9\-THC is delivered to the brain rapidly and
efficiently as would be expected of a highly lipid-soluble drug.

The petitioner provided a discussion of new, or less common,
routes and methods of administration being currently explored (pg.
57, line 1). These include vaporization for the inhalation route, as
well as rectal, sublingual, and transdermal routes.

DEA notes that respiratory effects are only part of the harmful
health effects of prolonged marijuana exposure, as described further
under factor 2 of this document. DEA also notes that at this time,
the majority of studies exploring the potential therapeutic uses of
marijuana use smoked marijuana, and the pharmacokinetics and
bioavailability from routes of administration other than smoked and
oral are not well-known.

The pharmacokinetics of smoked and orally ingested marijuana are
thoroughly reviewed in DHHS's review document.

Medical Utility

The petition filed by the Coalition to Reschedule Cannabis
(Marijuana) aims to repeal the rule placing marijuana in schedule I
of the CSA, based in part on the proposition that marijuana has an
accepted medical use in the United States. However DHHS has
concluded in its 2006 analysis that marijuana has no accepted
medical use in treatment in the United States. Following is a
discussion of the petitioner's specific points and a presentation of
DHHS's evaluation and recommendation on the question of accepted
medical use for marijuana.

The petitioner states (pg. 48, line 2), "Results from clinical
research demonstrated that both dronabinol and whole plant cannabis
can offer a safe and effective treatment for the following
illnesses: muscle spasm in multiple sclerosis, Tourette syndrome,
chronic pain, nausea and vomiting in HIV/AIDS and cancer
chemotherapy, loss of appetite from cancer, hyperactivity of the
bladder in patients with multiple sclerosis and spinal cord injury,
and dyskinesia caused by levodopa in Parkinson's disease."

To support its claim that marijuana has an accepted medical use
in the United States, the petitioner listed supporting evidence that
included the following:

Evidence from clinical research and reviews of earlier
clinical research (Exh. C, Section I (4, 6), pg. 29)

Acceptance of the medical use of marijuana by eight
states since 1996 and state officials in these states establishing
that marijuana has an accepted medical use in the United States
(Exh. C, Section I (1), pg. 13)

Increased recognition by health care professionals and
the medical community, including the Institute of Medicine (IOM)
(Exh. C, Section I (2), pg. 15)

DHHS states that a new drug application (NDA) for marijuana has
not been submitted to the FDA for any indication and thus no
medicinal product containing botanical cannabis has been approved
for marketing. Only small clinical studies published in the current
medical literature demonstrate that research with marijuana is being
conducted in humans in the United States under FDA-authorized
investigational new drug (IND) applications.

There are ongoing clinical studies of the potential utility of
marijuana in medical applications. DHHS states that in 2000, the
state of California established the Center for Medicinal Cannabis
Research (CMCR) which has funded studies on the potential use of
cannabinoids for the treatment of multiple sclerosis, neuropathic
pain, appetite suppression and cachexia, and severe pain and nausea
related to cancer or its treatment by chemotherapy. To date, though,
no NDAs utilizing marijuana for these indications have been
submitted to the FDA.

To establish accepted medical use, among other criteria, the
effectiveness of a drug must be established in well-controlled
scientific studies performed in a large number of patients. To date,
such studies have not been performed for marijuana. Small clinical
trial studies with limited patients and short duration such as those
cited by the petitioner are not sufficient to establish medical
utility. Larger studies of longer duration are needed to fully
characterize the drug's efficacy and safety profile. Anecdotal
reports, patients' self-reported effects, and isolated case reports
are not adequate evidence to support an accepted medical use of
marijuana (57 FR 10499, 1992).

In addition to demonstrating efficacy, adequate safety studies
must be performed to show that the drug is safe for treating the
targeted disease. DHHS states that safety studies for acute or
subchronic administration of marijuana have been carried out through
a limited number of Phase 1 clinical investigations approved by the
FDA, but there have been no NDA-quality studies that have
scientifically assessed the efficacy and full safety profile of
marijuana for any medical condition.

DEA further notes that a number of clinical studies from CMCR
have been discontinued. Most of these discontinuations were due to

The petitioner states that the pharmacological effects are well
established for marijuana and [Delta]\9\-THC, using the argument
that Marinol (containing synthetic [Delta]\9\-THC, known generically
as dronabinol) and Cesamet (containing nabilone, a synthetic
cannabinoid not found in marijuana) are approved for several
therapeutic indications. The approvals of Marinol and Cesamet were
based on well-controlled clinical studies that established the
efficacy and safety of these drugs as a medicine. Smoked marijuana
has not been demonstrated to be safe and effective in treating these
medical conditions. Marijuana is a drug substance composed of
numerous cannabinoids and other constituents; hence the safety and
efficacy of marijuana cannot be evaluated solely on the effects of
[Delta]\9\-THC. Adequate and well-controlled studies must be
performed with smoked marijuana to establish efficacy and safety.
DHHS states that there is a lack of accepted safety for the use of
marijuana under medical supervision.

The petitioner has not submitted any new data meeting the
requisite scientific standards to support the claim that marijuana
has an accepted medical use in the United States. Hence, the new
information provided by the petitioner does not change the federal
government's evaluation of marijuana's medical use in the United
States.

Petitioner's claim of acceptance of the medical use of
marijuana by eight states since 1996 and state officials in these
states establishing that marijuana has an accepted medical use in
the United States

Petitioner argues that, "[t]he acceptance of cannabis's medical
use by eight states since 1996 and the experiences of patients,
doctors, and state officials in these states establish marijuana's
accepted medical use in the United States." Petition at 10, 13.
This argument is contrary to the CSA's statutory scheme. The CSA
does not assign to the states the authority to make findings
relevant to CSA scheduling determinations. Rather, the CSA expressly
delegates the task of making such findings--including whether a
substance has any currently accepted medical use in treatment in the
United States--to the Attorney General. 21 U.S.C. 811(a). The CSA
also expressly tasks the Secretary of DHHS to provide a scientific
and medical evaluation and scheduling recommendations to inform the
Attorney General's findings. 21 U.S.C. 811(b); see also 21 C.F.R.
308.43. That Congress explicitly provided scheduling authority to
these two federal entities in this comprehensive and exclusive
statutory scheme precludes the argument that state legislative
action can establish accepted medical use under the CSA.

The CSA explicitly provides that in making a scheduling
determination, the Attorney General shall consider the following
eight factors:

1. The drug's actual or relative potential for abuse

2. Scientific evidence of its pharmacological effect, if known;

3. The state of current scientific knowledge regarding the drug;

4. Its history and current pattern of abuse;

5. The scope, duration, and significance of abuse;

6. What, if any, risk there is to the public health;

7. The drug's psychic or physiological dependence liability; and

8. Whether the substance is an immediate precursor of a
substance already controlled under the CSA.

21 U.S.C. 811(c). These factors embody Congress's view of the
specialized agency expertise required for drug rescheduling
decisions. The CSA's statutory text thus further evidences that
Congress did not envision such a role for state law in establishing
the schedules of controlled substances under the CSA. See Krumm v.
Holder, 2009 WL 1563381, at *16 (D.N.M. 2009) ("The CSA does not
contemplate that state legislatures' determinations about the use of
a controlled substance can be used to bypass the CSA's rescheduling
process.").

The long-established factors applied by DEA for determining
whether a drug has a "currently accepted medical use" under the
CSA are:

1. The drug's chemistry must be known and reproducible;

2. There must be adequate safety studies;

3. There must be adequate and well-controlled studies proving
efficacy;

4. The drug must be accepted by qualified experts; and

5. The scientific evidence must be widely available.

57 FR 10,499, 10,506 (1992), ACT, 15 F.3d at 1135 (upholding these
factors as valid criteria for determining "currently accepted
medical use"). A drug will be deemed to have a currently accepted
medical use for CSA purposes only if all five of the foregoing
elements are demonstrated. The following is a summary of information
as it relates to each of these five elements.

1. The drug's chemistry must be known and reproducible

DHHS states that although the structures of many cannabinoids
found in marijuana have been characterized, a complete scientific
analysis of all the chemical components found in marijuana has not
been conducted.

DEA notes that in addition to changes due to its own genetic
plasticity, marijuana and its chemistry have been throughout the
ages, and continue to be, modified by environmental factors and
human manipulation (Paris and Nahas, 1984).

2. There must be adequate safety studies

DHHS states that safety studies for acute or subchronic
administration of marijuana have been carried out only through a
limited number of Phase 1 clinical investigations approved by the
FDA. There have been no NDA-quality studies that have scientifically
assessed the safety profile of marijuana for any medical condition.
DHHS also states that at this time, the known risks of marijuana use
have not been shown to be outweighed by specific benefits in well-
controlled clinical trials that scientifically evaluate safety and
efficacy.

DHHS further states that it cannot conclude that marijuana has
an acceptable level of safety without assurance of a consistent and
predictable potency and without proof that the substance is free of
contamination.

As discussed in Factors 1 and 2, current data suggest that
marijuana use produces adverse effects on the respiratory system,
memory and learning. Marijuana use is associated with dependence and
addiction. In addition, large epidemiological studies indicate that
marijuana use may exacerbate symptoms in individuals with
schizophrenia.

Therefore DHHS concludes that, even under medical supervision,
marijuana has not been shown to have an accepted level of safety.
Furthermore, if marijuana is to be investigated more widely for
medical use, information and data regarding the chemistry,
manufacturing, and specifications of marijuana must be developed.

3. There must be adequate and well-controlled studies proving
efficacy

DHHS states that no studies have been conducted with marijuana
showing efficacy for any indication in controlled, large scale,
clinical trials.

To establish accepted medical use, the effectiveness of a drug
must be established in well-controlled, well-designed, well-
conducted, and well-documented scientific studies, including studies
performed in a large number of patients (57 FR 10499, 1992). To
date, such studies have not been performed. The small clinical trial
studies with limited patients and short duration are not sufficient
to establish medical utility. Studies of longer duration are needed
to fully characterize the drug's efficacy and safety profile.
Scientific reliability must be established in multiple clinical
studies. Furthermore, anecdotal reports and isolated case reports
are not adequate evidence to support an accepted medical use of
marijuana (57 FR 10499, 1992). The evidence from clinical research
and reviews of earlier clinical research does not meet this
standard.

As noted, DHHS states that a limited number of Phase I
investigations have been conducted as approved by the FDA. Clinical
trials, however, generally proceed in three phases. See 21 C.F.R.
312.21 (2010). Phase I trials encompass initial testing in human
subjects, generally involving 20 to 80 patients. Id. They are
designed primarily to assess initial safety, tolerability,
pharmacokinetics, pharmacodynamics, and preliminary studies of
potential therapeutic benefit. (62 FR 66113, 1997). Phase II and
Phase III studies involve successively larger groups of patients:
usually no more than several hundred subjects in Phase II and
usually from several hundred to several thousand in Phase III. 21
C.F.R. 312.21. These studies are designed primarily to explore
(Phase II) and to demonstrate or confirm (Phase III) therapeutic
efficacy and benefit in patients. (62 FR 66113, 1997). No Phase II
or Phase III studies of marijuana have been conducted. Even in 2001,
DHHS acknowledged that there is "suggestive evidence that marijuana
may have beneficial

[[Page 40580]]

therapeutic effects in relieving spasticity associated with multiple
sclerosis, as an analgesic, as an antiemetic, as an appetite
stimulant and as a bronchodilator." (66 FR 20038, 2001). But there
is still no data from adequate and well-controlled clinical trials
that meets the requisite standard to warrant rescheduling.

DHHS states in a published guidance that it is committed to
providing "research-grade marijuana for studies that are the most
likely to yield usable, essential data" (DHHS, 1999). DHHS states
that the opportunity for scientists to conduct clinical research
with botanical marijuana has increased due to changes in the process
for obtaining botanical marijuana from NIDA, the only legitimate
source of the drug for research in the United States. It further
states that in May 1999, DHHS provided guidance on the procedures
for providing research-grade marijuana to scientists who intend to
study marijuana in scientifically valid investigations and well-
controlled clinical trials (DHHS, 1999).

4. The drug must be accepted by qualified experts

A material conflict of opinion among experts precludes a finding
that marijuana has been accepted by qualified experts (57 FR 10499,
1992). DHHS states that, at this time, it is clear that there is not
a consensus of medical opinion concerning medical applications of
marijuana, even under conditions where its use is severely
restricted. DHHS also concludes that, to date, research on the
medical use of marijuana has not progressed to the point that
marijuana can be considered to have a "currently accepted medical
use" or a "currently accepted medical use with severe
restrictions."

5. The scientific evidence must be widely available

DHHS states that the scientific evidence regarding the safety or
efficacy of marijuana is typically available only in summarized
form, such as in a paper published in the medical literature, rather
than in a raw data format. As such, there is no opportunity for
adequate scientific scrutiny of whether the data demonstrate safety
or efficacy. Furthermore, as stated before, there have only been a
limited number of small clinical trials and no controlled, large-
scale clinical trials have been conducted with marijuana on its
efficacy for any indications or its safety.

In summary, from DHHS's statements on the five cited elements
required to make a determination of "currently accepted medical
use" for marijuana, DEA has determined that none has been
fulfilled. A complete scientific analysis of all the chemical
components found in marijuana is still missing. There has been no
NDA-quality study that has assessed the efficacy and full safety
profile of marijuana for any medical use. At this time, it is clear
that there is not a consensus of medical opinion concerning medical
applications of marijuana. To date, research on the medical use of
marijuana has not progressed to the point that marijuana can be
considered to have a "currently accepted medical use" or even a
"currently accepted medical use with severe restrictions." 21
U.S.C. 812(b)(2)(B)). Additionally, scientific evidence as to the
safety or efficacy of marijuana is not widely available.

Petitioner's claim of increased recognition by health
care professionals and the medical community, including the
Institute of Medicine (IOM)

The petitioner states (pg. 15 line 2), "Cannabis's accepted
medical use in the United States is increasingly recognized by
healthcare professionals and the medical community, including the
Institute of Medicine."

DHHS describes that in February 1997, a National Institutes of
Health (NIH)-sponsored workshop analyzed available scientific
evidence on the potential utility of marijuana. In March 1999, the
Institute of Medicine (IOM) issued a detailed report on the
potential medical utility of marijuana. Both reports concluded that
there need to be more and better studies to determine potential
medical applications of marijuana. The IOM report also recommended
that clinical trials should be conducted with the goal of developing
safe delivery systems (NIH, 1997; IOM, 1999).

DEA notes that in its recommendations, the 1999 IOM report
states,

If there is any future for marijuana as a medicine, it lies in its
isolated components, the cannabinoids and their synthetic
derivatives. Isolated cannabinoids will provide more reliable
effects than crude plant mixtures. Therefore, the purpose of
clinical trials of smoked marijuana would not be to develop
marijuana as a licensed drug but rather to serve as a first step
toward the development of nonsmoked rapid-onset cannabinoid delivery
systems.

Thus, while the IOM report did support further research into
therapeutic uses of cannabinoids, the IOM report did not "recognize
marijuana's accepted medical use" but rather the potential
therapeutic utility of cannabinoids.

DEA notes that the lists presented by the petitioner (pg. 16-18)
of "Organizations Supporting Access to Therapeutic Cannabis"
(emphasis added) and "[Organizations Supporting] No Criminal
Penalty" contain a majority of organizations that do not
specifically represent medical professionals. By contrast, the
petitioner also provides a list of "Organizations Supporting
Research on the Therapeutic Use of Cannabis" (emphasis added),
which does contain a majority of organizations specifically
representing medical professionals.

The petitioner discusses (pg. 20, line 11) the results of a
United States survey presented at the annual meeting of the American
Society of Addiction Medicine, and states that the study's results,

indicate that physicians are divided on the medical use of cannabis
(Reuters of 23 April 2001). Researchers at Rhode Island Hospital in
Providence asked 960 doctors about their attitude towards the
statement, "Doctors should be able to legally prescribe marijuana
as medical therapy." 36 percent of the responders agreed, 38
percent disagreed and 26 percent were neutral.

DEA notes that the results of the study, later published in full
(Charuvastra et al., 2005) show that a slight majority of medical
doctors polled were opposed to the legalization of medical
prescription of marijuana. This supports the finding that there is a
material conflict of opinion among medical professionals.

Under the petition's section C. I. 3., the petitioner proposes
both anecdotal self-reported effects by patients and clinical
studies. The petitioner states (pg. 22, line 2),

[. . .] an increasing number of patients have collected experience
with cannabis. Many reported benefits from its use. Some of this
experience has been confirmed in reports and clinical investigations
or stimulated clinical research that confirmed these patients'
experience on other patients suffering from the same disease.

Anecdotal self-reported effects by patients are not adequate
evidence for the determination of a drug's accepted medical use. DEA
previously ruled in its final order denying the petition of the
National Organization for Reform of Marijuana Laws (NORML) to
reschedule marijuana from Schedule I to Schedule II of the
Controlled Substances Act (57 FR 10499, 1992) that,

Lay testimonials, impressions of physicians, isolated case studies,
random clinical experience, reports so lacking in details they
cannot be scientifically evaluated, and all other forms of anecdotal
proof are entirely irrelevant.

DEA further explained in the same ruling that,

Scientists call [stories by marijuana users who claim to have been
helped by the drug] anecdotes. They do not accept them as reliable
proofs. The FDA's regulations, for example, provide that in deciding
whether a new drug is a safe and effective medicine, "isolated case
reports will not be considered." 21 CFR 314.126(e). Why do
scientists consider stories from patients and their doctors to be
unreliable?

First, sick people are not objective scientific observers,
especially when it comes to their own health. [. . .] Second, most
of the stories come from people who took marijuana at the same time
they took prescription drugs for their symptoms. [. . .] Third, any
mind-altering drug that produces euphoria can make a sick person
think he feels better. [. . .] Fourth, long-time abusers of
marijuana are not immune to illness.

[. . .] Thanks to scientific advances and to the passage of the
Federal Food, Drug and Cosmetic Act (FDCA) in 1906, 21 U.S.C. 301 et
seq., we now rely on rigorous scientific proof to assure the safety
and effectiveness of new drugs. Mere stories are not considered an
acceptable way to judge whether dangerous drugs should be used as
medicines.

Thus, patients' anecdotal experiences with marijuana are not
adequate evidence when evaluating whether marijuana has a currently
accepted medical use.

In summary, marijuana contains some 483 natural constituents and
exists in several forms, including dried leaves and flowering

[[Page 40581]]

tops, hashish and hashish oil. It is generally smoked as a
cigarette. Research with marijuana is being conducted in humans in
the United States under FDA-authorized IND applications, and using
marijuana cigarettes provided by NIDA. Adequate studies have not
been published to support the safety and efficacy of marijuana as a
medicine. No NDA for marijuana has been submitted to the FDA for any
indication and thus no medicinal product containing botanical
cannabis has been approved for marketing. DEA notes that state laws
do not establish a currently accepted medical use under federal law.
Furthermore, DEA previously ruled that anecdotal self-reported
effects by patients are not adequate evidence of a currently
accepted medical use under federal law. A material conflict of
opinion among experts precludes a finding that marijuana has been
accepted by qualified experts. At present, there is no consensus of
medical opinion concerning medical applications of marijuana. In
short, the limited number of clinical trials involving marijuana
that have been conducted to date--none of which have progressed
beyond phase 1 of the three phases needed to demonstrate safety and
efficacy for purposes of FDA approval--fails by a large measure to
provide a basis for any alteration of the prior conclusions made by
HHS and DEA (in 1992 and in 2001) that marijuana has no currently
accepted medical use in treatment in the United States.

FACTOR 4: ITS HISTORY AND CURRENT PATTERN OF ABUSE

Marijuana use has been relatively stable from 2002 to 2009, and
it continues to be the most widely used illicit drug. According to
the NSDUH, there were 2.4 million new users (6,000 initiates per
day) in 2009 and 16.7 million current (past month) users of
marijuana aged 12 and older. Past month use of marijuana was
statistically significantly higher in 2009 (16.7 million) than in
2008 (15.2 million), according to NSDUH. An estimated 104.4 million
Americans age 12 or older had used marijuana or hashish in their
lifetime and 28.5 million had used it in the past year. In 2008,
most (62.2 percent) of the 2.2 million new users were less than 18
years of age. In 2008, marijuana was used by 75.7 percent of current
illicit drug users and was the only drug used by 57.3 percent of
these users. In 2008, among past year marijuana users aged 12 or
older, 15.0 percent used marijuana on 300 or more days within the
previous 12 months. This translates into 3.9 million people using
marijuana on a daily or almost daily basis over a 12-month period.
In 2008, among past month marijuana users, 35.7 percent (5.4
million) used the drug on 20 or more days in the past month.

Marijuana is also the illicit drug with the highest rate of past
year dependence or abuse. According to the 2009 NSDUH report, 4.3
million persons were classified with marijuana dependence or abuse
based on criteria specified in the Diagnostic and Statistical Manual
of Mental Disorders, 4th edition (DSM-IV).

According to the 2010 Monitoring the Future (MTF) survey,
marijuana is used by a large percentage of American youths. Among
students surveyed in 2010, 17.3 percent of eighth graders, 33.4
percent of tenth graders, and 43.8 percent of twelfth graders
reported lifetime use (i.e., any use in their lifetime) of
marijuana. In addition, 13.7, 27.5 and 34.8 percent of eighth, tenth
and twelfth graders, respectively, reported using marijuana in the
past year. A number of high-schoolers reported daily use in the past
month, including 1.2, 3.3 and 6.1 percent of eighth, tenth and
twelfth graders, respectively.

The prevalence of marijuana use and abuse is also indicated by
criminal investigations for which drug evidences were analyzed in
DEA and state laboratories. The National Forensic Laboratory System
(NFLIS), which compiles information on exhibits analyzed in state
and local law enforcement laboratories, showed that marijuana was
the most frequently identified drug from January 2001 through
December 2010: In 2010, marijuana accounted for 36.3 percent
(464,059) of all drug exhibits in NFLIS. Similar findings were
reported by the System to Retrieve Information from Drug Evidence
(STRIDE), a DEA database which compiles information on exhibits
analyzed in DEA laboratories, for the same reporting period. From
January 2001 through December 2010, marijuana was the most
frequently identified drug. In 2010, there were 11,293 marijuana
exhibits associated with 7,158 law enforcement cases representing
16.7 percent of all exhibits in STRIDE.

The high consumption of marijuana is being fueled by increasing
amounts of domestically grown marijuana as well as increased amounts
of foreign source marijuana being illicitly smuggled into the United
States. In 2009, the Domestic Cannabis Eradication and Suppression
Program (DCE/SP) reported that 9,980,038 plants were eradicated in
outdoor cannabis cultivation areas in the United States. Major
domestic outdoor cannabis cultivation areas were found in
California, Kentucky, Tennessee and Hawaii. Significant quantities
of marijuana were also eradicated from indoor cultivation
operations. There were 414,604 indoor plants eradicated in 2009
compared to 217,105 eradicated in 2000. Most foreign-source
marijuana smuggled into the United States enters through or between
points of entry at the United States-Mexico border. However, drug
seizure data show that the amount of marijuana smuggled into the
United States from Canada via the United States-Canada border has
risen to a significant level. In 2009, the Federal-wide Drug Seizure
System (FDSS) reported seizures of 1,910,600 kg of marijuana.

While most of the marijuana available in the domestic drug
markets is lower potency commercial-grade marijuana, usually derived
from outdoor cannabis grow sites in Mexico and the United States, an
increasing percentage of the available marijuana is high potency
marijuana derived from indoor, closely controlled cannabis
cultivation in Canada and the United States. The rising prevalence
of high potency marijuana is evidenced by a nearly two-fold increase
in average potency of tested marijuana samples, from 4.87 percent
[Delta]\9\-THC in 2000 to 8.49 percent [Delta]\9\-THC in 2008.

In summary, marijuana is the most commonly used illegal drug in
the United States, and it is used by a large percentage of American
high-schoolers. Marijuana is the most frequently identified drug in
state, local and federal forensic laboratories, with increasing
amounts both of domestically grown and of illicitly smuggled
marijuana. An observed increase in the potency of seized marijuana
also raises concerns.

FACTOR 5: THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

Abuse of marijuana is widespread and significant. DHHS presented
data from the NSDUH, and DEA has updated this information. As
previously noted, according to the NSDUH, in 2009, an estimated
104.4 million Americans age 12 or older had used marijuana or
hashish in their lifetime, 28.5 million had used it in the past
year, and 16.7 million (6.6 percent) had used it in the past month.
In 2008, an estimated 15.0 percent of past year marijuana users aged
12 or older used marijuana on 300 or more days within the past 12
months. This translates into 3.9 million persons using marijuana on
a daily or almost daily basis over a 12-month period. In 2008, an
estimated 35.7 percent (5.4 million) of past month marijuana users
aged 12 or older used the drug on 20 or more days in the past month
(SAMHSA, NSDUH and TEDS). Chronic use of marijuana is associated
with a number of health risks (see Factors 2 and 6).

Marijuana's widespread availability is being fueled by
increasing marijuana production domestically and increased illicit
importation from Mexico and Canada. Domestically both indoor and
outdoor grow sites have been encountered. In 2009, nearly 10 million
marijuana plants were seized from outdoor grow sites and over
410,000 were seized from indoor sites for a total of over 10 million
plants in 2009 compared to about 2.8 million plants in 2000
(Domestic Cannabis Eradication/Suppression Program). An increasing
percentage of the available marijuana being trafficked in the United
States is higher potency marijuana derived from the indoor, closely
controlled cultivation of marijuana plants in both the US and Canada
(Domestic Cannabis Eradication/Suppression Program) and the average
percentage of [Delta]\9\-THC in seized marijuana increased almost
two-fold from 2000 to 2008 (The University of Mississippi Potency
Monitoring Project). Additional studies are needed to clarify the
impact of greater potency, but DEA notes one study showing that
higher levels of [Delta]\9\-THC in the body are associated with
greater psychoactive effects (Harder and Rietbrock, 1997), which can
be correlated with higher abuse potential (Chait and Burke, 1994).

Data from TEDS show that in 2008, 17.2 percent of all admissions
were for primary marijuana abuse. In 2007, more than half of the
drug-related treatment admissions involving individuals under the
age of 15 (60.8 percent) and more than half of the drug-related
treatment admissions involving individuals 15 to 19 years of age
(55.9 percent), were for primary marijuana abuse. In 2007, among the
marijuana/hashish admissions (286,194), 25.1 percent began using
marijuana at age 12 or younger.

In summary, the recent statistics from these various surveys and
databases show that

[[Page 40582]]

marijuana continues to be the most commonly used illicit drug, with
significant rates of heavy use and dependence in teenagers and
adults.

The petitioner states, "The use and abuse of cannabis has been
widespread in the United States since national drug use surveys
began in the 1970s. A considerable number of cannabis users suffer
from problems that meet the criteria for abuse. However, the large
majority of cannabis users do not experience any relevant problems
related to their use." (pg. 4, line 31).

Petitioner acknowledges that a considerable number of cannabis
users suffer from problems that meet the criteria for abuse. DEA
provides data under this Factor, as well as Factors 1, 2, and 7,
that support this undisputed issue. Briefly, current data suggest
that marijuana use produces adverse effects on the respiratory
system, memory and learning. Marijuana use is associated with
dependence and addiction. In addition, large epidemiological studies
indicate that marijuana use may exacerbate symptoms in individuals
with schizophrenia, and may precipitate schizophrenic disorders in
those individuals who are vulnerable to developing psychosis.

FACTOR 6: WHAT, IF ANY, RISK THERE IS TO THE PUBLIC HEALTH

The risk marijuana poses to the public health may manifest
itself in many ways. Marijuana use may affect the physical and/or
psychological functioning of an individual user, but may also have
broader public impacts, for example, from a marijuana-impaired
driver. The impacts of marijuana abuse and dependence are more
disruptive for an abuser, but also for the abuser's family, friends,
work environment, and society in general. Data regarding marijuana
health risks are available from many sources, including forensic
laboratory analyses, crime laboratories, medical examiners, poison
control centers, substance abuse treatment centers, and the
scientific and medical literature. Risks have been associated with
both acute and chronic marijuana use, including risks for the
cardiovascular and respiratory systems, as well as risks for mental
health and cognitive function and risks related to prenatal exposure
to marijuana. The risks of marijuana use and abuse have previously
been discussed in terms of the scientific evidence of its
pharmacological effects on physical systems under Factor 2. Below,
some of the risks of marijuana use and abuse are discussed in
broader terms of the effects on the individual user and the public
from acute and chronic use of the drug.

Risks Associated with Acute Use of Marijuana

DHHS states that acute use of marijuana impairs psychomotor
performance, including performance of complex tasks, which makes it
inadvisable to operate motor vehicles or heavy equipment after using
marijuana (Ramaekers et al., 2004). DHHS further describes a study
showing that acute administration of smoked marijuana impairs
performance on tests of learning, associative processes, and
psychomotor behavior (Block et al., 1992). DHHS also describes
studies showing that administration to human volunteers of
[Delta]\9\-THC in a smoked marijuana cigarette produced impaired
perceptual motor speed and accuracy, two skills that are critical to
driving ability (Kurzthaler et al., 1999) and produced increases in
disequilibrium measures, as well as in the latency in a task of
simulated vehicle braking, at a rate comparable to an increase in
stopping distance of 5 feet at 60 mph (Liguori et al., 1998).

The petitioner states that (pg., 65, line 10), "Although the
ability to perform complex cognitive operations is assumed to be
impaired following acute marijuana smoking, complex cognitive
performance after acute marijuana use has not been adequately
assessed under experimental conditions." As described above, DHHS
presents evidence of marijuana's acute effects on complex cognitive
tasks.

DHHS states that dysphoria and psychological distress, including
prolonged anxiety reactions, are potential responses in a minority
of individuals who use marijuana (Haney et al., 1999). DEA notes
reviews of studies describing that some users report unpleasant
psychological reactions. Acute anxiety reactions to cannabis may
include restlessness, depersonalization, derealization, sense of
loss of control, fear of dying, panic and paranoid ideas (see
reviews by Thomas, 1993 and Weil, 1970).

DEA notes a review of studies showing that the general
depressant effect of moderate to high doses of cannabis might
contribute to slowed reaction times, inability to maintain
concentration and lapses in attention (see review by Chait and
Pierri, 1992). The review suggests that fine motor control and
manual dexterity are generally adversely affected although simple
reaction time may or may not be. DEA also notes studies showing that
choice or complex reaction time is more likely to be affected, with
reaction time consistently increasing with the difficulty of the
task (e.g., Block and Wittenborn, 1985).

DEA also notes additional studies showing marijuana use
interferes with the ability to operate motor vehicles. Studies show
that marijuana use can cause impairment in driving (Robbe and
O'Hanlon, 1999). The National Highway Traffic Safety Administration
(NHTSA) conducted a study with the Institute for Human
Psychopharmacology at Maastricht University in the Netherlands
(Robbe and O'Hanlon, 1999) to evaluate the effects of low and high
doses of smoked [Delta]\9\-THC alone and in combination with alcohol
on the following tests: 1) the Road Tracking Test, which measures
the driver's ability to maintain a constant speed of 62 mph and a
steady lateral position between the boundaries of the right traffic
lane; and 2) the Car Following Test, which measures a driver's
reaction times and ability to maintain distance between vehicles
while driving 164 ft behind a vehicle that executes a series of
alternating accelerations and decelerations. Mild to moderate
impairment of driving was observed in the subjects after treatment
with marijuana. The study found that marijuana in combination with
alcohol had an additive effect resulting in severe driving
impairment.

DEA also notes a study by Bedard and colleagues (2007), which
used a cross-sectional, case-control design with drivers aged 20-49
who were involved in a fatal crash in the United States from 1993 to
2003. Drivers were included if they had been tested for the presence
of cannabis and had a confirmed blood alcohol concentration of zero.
Cases were drivers who had at least one potentially unsafe driving
action recorded in relation to the crash (e.g., speeding); controls
were drivers who had no such driving action recorded. Authors
calculated the crude and adjusted odds ratios (ORs) of any
potentially unsafe driving action in drivers who tested positive for
cannabis but negative for alcohol consumption. Five percent of
drivers tested positive for cannabis. The crude OR of a potentially
unsafe action was 1.39 (99 percent CI = 1.21-1.59) for drivers who
tested positive for cannabis. Even after controlling for age, sex,
and prior driving record, the presence of cannabis remained
associated with a higher risk of a potentially unsafe driving action
(1.29, 99 percent CI = 1.11-1.50). Authors of the study concluded
that cannabis had a negative effect on driving, as predicted from
various human performance studies.

In 2001, estimates derived from the United States Census Bureau
and Monitoring the Future show that approximately 600,000 of the
nearly 4 million United States high-school seniors drive under the
influence of marijuana. Approximately 38,000 seniors reported that
they had crashed while driving under the influence of marijuana in
2001 (MTF, 2001).

DEA further notes studies suggesting that marijuana can affect
the performance of pilots. Yeswavage and colleagues (1985) evaluated
the acute and delayed effects of smoking one marijuana cigarette
containing 1.9 percent [Delta]\9\-THC (19 mg of [Delta]\9\-THC) on
the performance of aircraft pilots. Ten subjects were trained in a
flight simulator prior to marijuana exposure. Flight simulator
performance was measured by the number of aileron (lateral control)
and elevator (vertical control) and throttle changes, the size of
these control changes, the distance off the center of the runaway on
landing, and the average lateral and vertical deviation from an
ideal glideslope and center line over the final mile of the
approach. Compared to the baseline performance, significant
differences occurred at 4 hours. Most importantly, at 24 hours after
a single marijuana cigarette, there were significant impairments in
the number and size of aileron changes, size of elevator changes,
distance off-center on landing, and vertical and lateral deviations
on approach to landing. Interestingly, despite these performance
deficits, the pilots reported no significant subjective awareness of
their impairments at 24 hours.

DEA notes a review of the contaminants and adulterants that can
be found in marijuana (McPartland, 2002). In particular, DEA notes
that many studies have reported contamination of both illicit and
NIDA-grown marijuana with microbial contaminants, bacterial or
fungal (McLaren et al., 2008; McPartland, 1994, 2002; Ungerleider et
al., 1982; Taylor et al., 1982; Kurup et al., 1983). In a study by
Kagen and

[[Page 40583]]

colleagues (1983), fungi was found in 13 of the 14 samples, and
evidence of exposure to Aspergillus fungi was found in the majority
of marijuana smokers (13 of 23), but only one of the 10 control
participants. Aspergillus can cause aspergillosis, a fatal lung
disease and DEA notes studies suggesting an association between this
disease and cannabis smoking among patients with compromised immune
systems (reviewed in McLaren et al., 2008). Other microbial
contaminants include bacteria such as Klebsiella pneumoniae,
salmonella enteritidis, and group D Streptococcus (Ungerlerder et
al., 1982; Kagen et al., 1983; Taylor et al., 1982). DEA notes
reports that Salmonella outbreaks have been linked to marijuana
(Taylor et al., 1982, CDC, 1981).

Risks Associated with Chronic Use of Marijuana

DHHS states that chronic exposure to marijuana smoke is
considered to be comparable to tobacco smoke with respect to
increased risk of cancer and lung damage. DEA notes studies showing
that marijuana smoke contains several of the same carcinogens and
co-carcinogens as tobacco smoke and suggesting that pre-cancerous
lesions in bronchial epithelium also seem to be caused by long-term
marijuana smoking (Roth et al., 1998). DEA also notes the
publication of a recent case-control study of lung cancer in adults
(Aldington et al., 2008), in which users reporting over 10.5 joint-
years of exposure had a significantly increased risk of developing
lung cancer, leading the study's authors to conclude that long-term
cannabis use increases the risk of lung cancer in young adults. In
addition, a distinctive marijuana withdrawal syndrome has been
identified, indicating that marijuana produces physical dependence
(Budney et al., 2004), as described in Factor 7.

DHHS further quotes the Diagnostic and Statistical Manual (DSM-
IV-TR, 2000) of the American Psychiatric Association, which states
that the consequences of cannabis abuse are as follows:

[P]eriodic cannabis use and intoxication can interfere with
performance at work or school and may be physically hazardous in
situations such as driving a car. Legal problems may occur as a
consequence of arrests for cannabis possession. There may be
arguments with spouses or parents over the possession of cannabis in
the home or its use in the presence of children. When psychological
or physical problems are associated with cannabis in the context of
compulsive use, a diagnosis of Cannabis Dependence, rather than
Cannabis Abuse, should be considered.

Individuals with Cannabis Dependence have compulsive use and
associated problems. Tolerance to most of the effects of cannabis
has been reported in individuals who use cannabis chronically. There
have also been some reports of withdrawal symptoms, but their
clinical significance is uncertain. There is some evidence that a
majority of chronic users of cannabinoids report histories of
tolerance or withdrawal and that these individuals evidence more
severe drug-related problems overall. Individuals with Cannabis
Dependence may use very potent cannabis throughout the day over a
period of months or years, and they may spend several hours a day
acquiring and using the substance. This often interferes with
family, school, work, or recreational activities. Individuals with
Cannabis Dependence may also persist in their use despite knowledge
of physical problems (e.g., chronic cough related to smoking) or
psychological problems (e.g., excessive sedation and a decrease in
goal-oriented activities resulting from repeated use of high doses).

The petitioner cited "The Missoula Chronic Clinical Cannabis
Use Study" as evidence that long-term use of marijuana does not
cause significant harm in patients (Russo et al., 2002). DEA notes
that this article describes the case histories and clinical
examination of only four patients that were receiving marijuana
cigarettes from the National Institute on Drug Abuse for a variety
of medical conditions. The number of patients included in the study
is not adequate for this evaluation.

The petitioner states, "Studies have shown the long-term use of
cannabis to be safe. In contrast to many other medicinal drugs, the
long-term use of cannabis does not harm stomach, liver, kidneys and
heart." (Exh. C, Section II (10), pg. 66).

However, DHHS states that marijuana has not been shown to have
an accepted level of safety for medical use. There have been no NDA-
quality studies that have scientifically assessed the full safety
profile of marijuana for any medical condition. DEA notes in
addition, as described above, the risks associated with chronic
marijuana use, including, as described in Factor 2, risks for the
cardiovascular and respiratory systems, as well as risks for mental
health and cognitive function and risks related to prenatal exposure
to marijuana.

Marijuana as a "Gateway Drug"

A number of studies have examined the widely held premise that
marijuana use leads to subsequent abuse of other illicit drugs, thus
functioning as a "gateway drug." DHHS discussed a 25-year study of
1,256 New Zealand children, Fergusson et al. (2005), which concluded
that the use of marijuana correlates to an increased risk of abuse
of other drugs. Other studies, however, do not support a direct
causal relationship between regular marijuana use and other illicit
drug abuse. DHHS cited the IOM report (1999), which states that
marijuana is a "gateway drug" in the sense that its use typically
precedes rather than follows initiation of other illicit drug use.
However, as cited by DHHS, the IOM states that, "[t]here is no
conclusive evidence that the drug effects of marijuana are causally
linked to the subsequent abuse of other illicit drugs." DHHS noted
that for most studies that test the hypothesis that marijuana causes
abuse of harder drugs, the determinative measure for testing this
hypothesis is whether marijuana leads to "any drug use" rather
than that marijuana leads to "drug abuse and dependence" as
defined by DSM-IV criteria.

FACTOR 7: ITS PSYCHIC OR PHYSIOLOGICAL DEPENDENCE LIABILITY

DHHS states that many medications that are not associated with
abuse or addiction, such as antidepressants, beta-blockers, and
centrally acting antihypertensive drugs, can produce physical
dependence and withdrawal symptoms after chronic use. However,
psychological and physical dependence of drugs that have abuse
potential are important factors contributing to increased or
continued drug taking. This section provides scientific evidence
that marijuana causes physical and psychological dependence.

Physiological (Physical) Dependence in Humans

Physical dependence is a state of adaptation manifested by a
drug class-specific withdrawal syndrome produced by abrupt
cessation, rapid dose reduction, decreasing blood level of the drug,
and/or administration of an antagonist (American Academy of Pain
Medicine, American Pain Society and American Society of Addiction
Medicine consensus document, 2001).

DHHS states that long-term, regular use of marijuana can lead to
physical dependence and withdrawal following discontinuation as well
as psychic addiction or dependence. The marijuana withdrawal
syndrome consists of symptoms such as restlessness, irritability,
mild agitation, insomnia, EEG disturbances, nausea, cramping and
decrease in mood and appetite that may resolve after 4 days, and may
require in-hospital treatment (Haney et al., 1999). It is distinct
and mild compared to the withdrawal syndromes associated with
alcohol and heroin use (Budney et al., 1999; Haney et al., 1999).
DEA notes that Budney et al. (1999) examined the withdrawal
symptomatology in 54 chronic marijuana abusers seeking treatment for
their dependence. The majority of the subjects (85 percent) reported
that they had experienced symptoms of at least moderate severity.
Fifty seven percent (57 percent) reported having six or more
symptoms of a least moderate severity while 47 percent experienced
four or more symptoms rated as severe. The most reported mood
symptoms associated with the

[[Page 40584]]

withdrawal were irritability, nervousness, depression, and anger.
Some of the other behavioral characteristics of the marijuana
withdrawal syndrome were craving, restlessness, sleep disruptions,
strange dreams, changes in appetite, and violent outbursts.

DHHS discusses a study by Lane and Phillips-Bute (1998) which
describes milder cases of dependence including symptoms that are
comparable to those from caffeine withdrawal, including decreased
vigor, increased fatigue, sleepiness, headache, and reduced ability
to work. The marijuana withdrawal syndrome has been reported in
adolescents who were admitted for substance abuse treatment or in
individuals who had been given marijuana on a daily basis during
research conditions. Withdrawal symptoms can also be induced in
animals following administration of a cannabinoid antagonist after
chronic [Delta]\9\-THC administration (Maldonado, 2002; Breivogel et
al., 2003). DHHS also discusses a study comparing marijuana and
tobacco withdrawal symptoms in humans (Vandrey et al., 2005) which
demonstrated that the magnitude and time course of the two
withdrawal syndromes are similar.

DHHS states that a review by Budney and colleagues (2004) of
studies of cannabinoid withdrawal, with a particular emphasis on
human studies, led to the recommendation that the Diagnostic and
Statistical Manual of Mental Disorders (DSM) introduce a listing for
cannabis withdrawal. In this listing, common symptoms would include
anger or aggression, decreased appetite or weight loss,
irritability, nervousness/anxiety, restlessness and sleep
difficulties including strange dreams. Less common symptoms/
equivocal symptoms would include chills, depressed mood, stomach
pain, shakiness and sweating.

Psychological Dependence in Humans

In addition to physical dependence, DHHS states that long-term,
regular use of marijuana can lead to psychic addiction or
dependence. Psychological dependence on marijuana is defined by the
American Psychiatric Association in the DSM-IV and cited by DHHS.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-
IV) is published by the American Psychiatric Association (2000), and
provides diagnostic criteria to improve the reliability of
diagnostic judgment of mental disorders by mental health
professionals. DSM-IV currently defines "Cannabis Dependence"
(DSM-IV diagnostic category 304.30) as follows:

Cannabis dependence: A destructive pattern of cannabis use,
leading to clinically significant impairment or distress, as
manifested by three (or more) of the following, occurring when the
cannabis use was at its worst:

1. Cannabis tolerance, as defined by either of the following:

a. A need for markedly increased amounts of cannabis to achieve
intoxication,

b. Markedly diminished effect with continued use of the same
amount of cannabis.

2. Greater use of cannabis than intended: Cannabis was often
taken in larger amounts or over a longer period than was intended.

3. Unsuccessful efforts to cut down or control cannabis use:
Persistent desire or unsuccessful efforts to cut down or control
cannabis use.

4. Great deal of time spent in using cannabis, or recovering
from hangovers.

5. Cannabis caused reduction in social, occupational or
recreational activities: Important social, occupational, or
recreational activities given up or reduced because of cannabis use.

6. Continued using cannabis despite knowing it caused
significant problems: Cannabis use is continued despite knowledge of
having a persistent or recurrent physical or psychological problem
that is likely to have been worsened by cannabis.

In addition, the DSM-IV added a specifier to this diagnostic by
which it can be with or without physiological (physical) dependence.

DEA notes additional clinical studies showing that frequency of
[Delta]\9\-THC use (most often as marijuana) escalates over time.
Individuals increase the number, doses, and potency of marijuana
cigarettes. Several studies have reported that patterns of marijuana
smoking and increased quantity of marijuana smoked were related to
social context and drug availability (Kelly et al., 1994; Mendelson
and Mello, 1984; Mello, 1989).

DEA further notes that Budney et al. (1999) reported that 93
percent of marijuana-dependent adults seeking treatment reported
experiencing mild craving for marijuana, and 44 percent rated their
past craving as severe. Craving for marijuana has also been
documented in marijuana users not seeking treatment (Heishman et
al., 2001). Two hundred seventeen marijuana users completed a 47-
item Marijuana Craving Questionnaire and forms assessing
demographics, drug use history, marijuana-quit attempts and current
mood. The results indicate that craving for marijuana was
characterized by 1) the inability to control marijuana use
(compulsivity); 2) the use of marijuana in anticipation of relief
from withdrawal or negative mood (emotionality); 3) anticipation of
positive outcomes from smoking marijuana (expectancy); and 4)
intention and planning to use marijuana for positive outcomes
(purposefulness).

In summary, long-term, regular use of marijuana can lead to
physical dependence and withdrawal following discontinuation as well
as psychic addiction or dependence.

FACTOR 8: WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A
SUBSTANCE ALREADY CONTROLLED UNDER THE CSA

Marijuana is not an immediate precursor of any controlled
substance.

DETERMINATION

After consideration of the eight factors discussed above and of
DHHS's recommendation, DEA finds that marijuana meets the three
criteria for placing a substance in Schedule I of the CSA under 21
U.S.C. 812(b)(1):

1. Marijuana has a high potential for abuse

Marijuana is the most highly abused and trafficked illicit
substance in the United States. Approximately 16.7 million
individuals in the United States (6.6 percent of the United States
population) used marijuana monthly in 2009. A 2009 national survey
that tracks drug use trends among high school students showed that
by 12th grade, 32.8 percent of students reported having used
marijuana in the past year, 20.6 percent reported using it in the
past month, and 5.2 percent reported having used it daily in the
past month. Its widespread availability is being fueled by
increasing marijuana production domestically and increased
trafficking from Mexico and Canada.

Marijuana has dose-dependent reinforcing effects that encourage
its abuse. Both clinical and preclinical studies have clearly
demonstrated that marijuana and its principle psychoactive
constituent, [Delta]\9\-THC, possess the pharmacological attributes
associated with drugs of abuse. They function as discriminative
stimuli and as positive reinforcers to maintain drug use and drug-
seeking behavior.

Significant numbers of chronic users of marijuana seek substance
abuse treatment. Compared to all other specific drugs included in
the 2008 NSDUH survey, marijuana had the highest levels of past year
dependence and abuse.

2. Marijuana has no currently accepted medical use in treatment in the
United States

DHHS states that the FDA has not evaluated nor approved an NDA
for marijuana. The long-established factors applied by DEA for
determining whether a drug has a "currently accepted medical use"
under the CSA are as follows. A drug will be deemed to have a
currently accepted medical use for CSA purposes only if all of the
following five elements have been satisfied. As set forth below,
none of these elements has been fulfilled:

i. The drug's chemistry must be known and reproducible

Although the structures of many cannabinoids found in marijuana
have been characterized, a complete scientific analysis of all the
chemical components found in marijuana has not been conducted.
Furthermore, many variants of the marijuana plant are found due to
its own genetic plasticity and human manipulation.

ii. There must be adequate safety studies

Safety studies for acute or sub-chronic administration of
marijuana have been carried out through a limited number of Phase I
clinical investigations approved by the FDA, but there have been no
NDA-quality studies that have scientifically assessed the full
safety profile of marijuana for any medical condition. Large,
controlled studies have not been conducted to evaluate the risk-
benefit ratio of marijuana use, and any potential benefits
attributed to marijuana use currently do not outweigh the known
risks.

iii. There must be adequate and well-controlled studies proving
efficacy

DHHS states that there have been no NDA-quality studies that
have scientifically assessed the efficacy of marijuana for any
medical condition. To establish accepted medical use, the
effectiveness of a drug must be established in well-controlled,
well-

[[Page 40585]]

designed, well-conducted, and well-documented scientific studies,
including studies performed in a large number of patients. To date,
such studies have not been performed for any indications.

Small clinical trial studies with limited patients and short
duration are not sufficient to establish medical utility. Studies of
longer duration are needed to fully characterize the drug's efficacy
and safety profile. Scientific reliability must be established in
multiple clinical studies. Anecdotal reports and isolated case
reports are not sufficient evidence to support an accepted medical
use of marijuana. The evidence from clinical research and reviews of
earlier clinical research does not meet the requisite standards.

iv. The drug must be accepted by qualified experts

At this time, it is clear that there is no consensus of opinion
among experts concerning medical applications of marijuana. To date,
research on the medical use of marijuana has not progressed to the
point that marijuana can be considered to have a "currently
accepted medical use" or a "currently accepted medical use with
severe restrictions.

v. The scientific evidence must be widely available

DHHS states that the scientific evidence regarding the safety
and efficacy of marijuana is typically available only in summarized
form, such as in a paper published in the medical literature, rather
than in a raw data format. In addition, as noted, there have only
been a limited number of small clinical trials and no controlled,
large scale, clinical trials have been conducted with marijuana on
its efficacy for any indications or its safety.

3. There is a lack of accepted safety for use of marijuana under
medical supervision

At present, there are no FDA-approved marijuana products, nor is
marijuana under NDA evaluation at the FDA for any indication.
Marijuana does not have a currently accepted medical use in
treatment in the United States or a currently accepted medical use
with severe restrictions. The Center for Medicinal Cannabis Research
in California, among others, is conducting research with marijuana
at the IND level, but these studies have not yet progressed to the
stage of submitting an NDA. Current data suggest that marijuana use
produces adverse effects on the respiratory system, memory and
learning. Marijuana use is associated with dependence and addiction.
In addition, very large epidemiological studies indicate that
marijuana use may be a causal factor for the development of
psychosis in individuals predisposed to develop psychosis and may
exacerbate psychotic symptoms in individuals with schizophrenia.
Thus, at this time, the known risks of marijuana use have not been
shown to be outweighed by specific benefits in well-controlled
clinical trials that scientifically evaluate safety and efficacy. In
sum, at present, marijuana lacks an acceptable level of safety even
under medical supervision.

Department of Health and Human Services (2006). Basis For The
Recommendation For Maintaining Marijuana In Schedule I Of The
Controlled Substances Act.

Department of Health and Human Services. Announcement of the
Department of Health and Human Services Guidance on Procedures for
the Provision of Marijuana for Medical Research. May 21, 1999.
(http://grants.nih.gov/grants/guide/notice-files/not99-091.html).

Fried, P., Watkinson, B., James, D., and Gray, R. (2002). Current
and former marijuana use: preliminary findings of a longitudinal
study of effects on IQ in young adults. Canadian Medical Association
Journal. 166(7):887-891.

Hanus, L. and Subiv[aacute], D. (1989). The amount of main
cannabinoid substances in hemp cultivated for industrial fibre
production and their changes in the course of one vegetation period.
Acta Universitatis Palackianae Olomucensis Facultatis Medicae.
122:11-23.